Cinnoline compounds

ABSTRACT

The invention relatest to compounds of the formula (I) wherein either any one of G 1 , G 2 , G 3 , G 4  and G 5  is nitrogen and the other four are —CH—, or G 1 , G 2 , G 3 , G 4  and G 5  are all —CH—; Z is —O—, —NH—, —S—, —CH 2 — or a direct bond; Z is linked to any one of G 1 , G 2 , G 3  and G 4  which is a free carbon atom; n is an integer from 0 to 5; any of the substitutents R 1  may be attached at any free carbon atom of the indole, azaindole or indazole group; m is an integer from 0 to 3; R a  represents hydrogen; R b  represents hydrogen or another value as defined herein; R 1  represents hydrogen, oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 -alkyl, aminoC 1-4 alkyl, C 1-3 alkylaminoC 1-4 alkyl, di(C 1-3 alkyl)aminoC 1-4 alkyl, —C 1-5 alkyl(ring B) wherein ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinly, N-ethylpiperazinyl, morpholino and thiomorpholino; R 2  represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 aklylsulphanyl, —NR 3 R 4  (wherein R 3  and R 4 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), or R 5 X 1 — (wherein R 5  and X 1  are as defined herein) and salts thereof, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and the use of a compound of formula I in the manufacture of medicament for the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

The present invention relates to cinnoline derivatives, processes fortheir preparation, pharmaceutical compositions containing them as activeingredient, methods for the treatment of disease states associated withangiogenesis and/or increased vascular permeability, to their use asmedicaments and to their use in the manufacture of medicaments for usein the production of antiangiogenic and/or vascular permeabilityreducing effects in warm-blooded animals such as humans.

Normal angiogenesis plays an important role in a variety of processesincluding embryonic development, wound healing and several components offemale reproductive function. Undesirable or pathological angiogenesishas been associated with disease states including diabetic retinopathy,psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma andhaemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman,1995, Nature Medicine 1: 27-31). Alteration of vascular permeability isthought to play a role in both normal and pathological physiologicalprocesses (Cullinan-Bove et al, 1993, Endocrinology 133: 829-837; Sengeret al, 1993, Cancer and Metastasis Reviews, 12: 303-324). Severalpolypeptides with in vitro endothelial cell growth promoting activityhave been identified including, acidic and basic fibroblast growthfactors (aFGF & bFGF) and vascular endothelial growth factor (VEGF). Byvirtue of the restricted expression of its receptors, the growth, factoractivity of VEGF, in contrast to that of the FGFs, is relativelyspecific towards endothelial cells. Recent evidence indicates that VEGFis an important stimulator of both normal and pathological angiogenesis(Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995,Breast Cancer Research and Treatment, 36:139-155) and vascularpermeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024).Antagonism of VEGF action by sequestration of VEGF with antibody canresult in inhibition of tumour growth (Kim et al, 1993, Nature 362:841-844). Basic FGF (bFGF) is a potent stimulator of angiogenesis (e.g.Hayek et al, 1987, Biochem. Biophys. Res. Commun. 147: 876-880) andraised levels of FGFs have been found in the serum (Fujimoto et al,1991, Biochem. Biophys. Res. Commun. 180: 386-392) and urine (Nguyen etal, 1993, J. Natl. Cancer. Inst. 85: 241-242) of patients with cancer.

Receptor tyrosine kinases (RTKs) are important in the transmission ofbiochemical signals across the plasma membrane of cells. Thesetransmembrane molecules characteristically consist of an extracellularligand-binding domain connected through a segment in the plasma membraneto an intracellular tyrosine kinase domain. Binding of ligand to thereceptor results in stimulation of the receptor-associated tyrosinekinase activity which leads to phosphorylation of tyrosine residues onboth the receptor and other intracellular molecules. These changes intyrosine phosphorylation initiate a signaling cascade leading to avariety of cellular responses. To date, at least nineteen distinct RTKsubfamilies, defined by amino acid sequence homology, have beenidentified. One of these subfamilies is presently comprised by thefins-like tyrosine kinase receptor, Flt or Flt1, the kinase insertdomain-containing receptor, KDR (also referred to as Flk-1), and anotherfms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fltand KDR, have been shown to bind VEGF with high affinity (De Vries etal, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys.Res. Commun. 1992, 187: 1579-1586). Binding of VEGF to these receptorsexpressed in heterologous cells has been associated with changes in thetyrosine phosphorylation status of cellular proteins and calcium fluxes.

The present invention is based on the discovery of compounds thatsurprisingly inhibit the effects of VEGF, a property of value in thetreatment of disease states associated with angiogenesis and/orincreased vascular permeability such as cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation, excessive scar formation and adhesions, lymphoedema,endometriosis, dysfunctional uterine bleeding and ocular diseases withretinal vessel proliferation. Compounds of the present inventiongenerally possess higher potency against VEGF receptor tyrosine kinasethan against epidermal growth factor (EGF) receptor tyrosine kinase.Compounds of the invention which have been tested possess activityagainst VEGF receptor tyrosine kinase such that they may be used in anamount sufficient to inhibit VEGF receptor tyrosine kinase whilstdemonstrating no significant activity against EGF receptor tyrosinekinase. Compounds of the present invention generally possess higherpotency against VEGF receptor tyrosine kinase than against FGF R1receptor tyrosine kinase. Compounds of the invention which have beentested possess activity against VEGF receptor tyrosine kinase such thatthey may be used in an amount sufficient to inhibit VEGF receptortyrosine kinase whilst demonstrating no significant activity against FGFR¹ receptor tyrosine kinase.

According to one aspect of the present invention there is provided theuse of a compound of the formula I:

wherein:

-   either any one of G₁, G₂, G₃, G₄ and G₅ is nitrogen and the other    four are —CH—, or G₁, G₂, G₃, G₄ and G₅ are all —CH—;-   Z is —O—, —NH—, —S—, —CH₂— or a direct bond; Z is linked to any one    of G₁, G₂, G₃ and G₄ which is a free carbon atom;-   n is an integer from 0 to 5; any of the substitutents R¹ may be    attached at any free carbon atom of the indole, azaindole or    indazole group, such free carbon atoms may be G₁, G₂, G₃, G₄ or G₅    or may be at the 3-position of the indole, azaindole or indazole    group;-   m is an integer from 0 to 3;-   R^(a) represents hydrogen;-   R^(b) represents hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,    aminoC₁₋₄alkyl, C₁₋₃alkylaminoC₁₋₄alkyl,    di(C₁₋₃alkyl)aminoC₁₋₄alkyl, C₂₋₅alkenylaminoC₁₋₄alkyl,    C₂₋₅alkynylaminoC₁₋₄alkyl, —C₁₋₅alkyl(ring A) wherein ring A is    selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,    morpholino and thiomorpholino and wherein ring A may bear one or    more substituents selected from C₁₋₄alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl,    hydroxy, oxo, halogeno, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkylsulphonyl    and C₁₋₄alkanoyl;-   R¹ represents hydrogen, oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, aminoC₁₋₄alkyl,    C₁₋₃alkylaminoC₁₋₄alkyl, di(C₁₋₃alkyl)aminoC₁₋₄alkyl,    —C₁₋₅alkyl(ring B) wherein ring B is selected from azetidinyl,    pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl,    N-ethylpiperazinyl, morpholino and thiomorpholino;-   R² represents hydrogen, hydroxy, halogeno, cyano, nitro,    trifluoromethyl, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylsulphanyl, —NR³R⁴    (wherein R³ and R⁴, which may be the same or different, each    represents hydrogen or C₁₋₃alkyl), or R⁵X¹— (wherein X¹ represents a    direct bond, —O—, —CH₂—, —OC(O)—, —C(O)—, —S—, —SO—, —SO₂—,    —NR⁶C(O)—, —C(O)NR⁷—, —SO₂NR⁸—, —NR⁹SO₂— or —NR¹⁰— (wherein R⁶, R⁷,    R⁸, R⁹ and R¹⁰ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl), and R⁵ is selected from one of the following    twenty-two groups:-   1) hydrogen, oxiranylC₁₋₄alkyl or C₁₋₅alkyl which may be    unsubstituted or which may be substituted with one or more groups    selected from hydroxy, fluoro, chloro, bromo and amino;-   2) C₁₋₅alkylX²C(O)R¹¹ (wherein X² represents —O— or —NR¹²— (in which    R¹² represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹¹    represents C₁₋₃alkyl, —N¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵    which may be the same or different each represents hydrogen,    C₁₋₅alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   3) C₁₋₅alkylX³R¹⁶ (wherein X³ represents —O—, —S—, —SO—, —SO₂—,    —OC(O)—, —NR¹⁷C(O)—, —C(O)NR¹⁸—, —SO₂NR¹⁹—, —NR²⁰SO₂— or —NR²¹—    (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ represents    hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 4-, 5- or    6-membered saturated heterocyclic group with 1-2 heteroatoms,    selected independently from O, S and N, which C₁₋₃alkyl group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and    C₁₋₄alkoxy and which cyclic group may bear 1 or 2 substituents    selected from oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl,    C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl));-   4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²² (wherein X⁴ and X⁵ which may be the    same or different are each —O—, —S—, —SO—, —SO₂—, —NR²³C(O)—,    —C(O)NR²⁴—, —SO₂NR²⁵, —NR²⁶SO₂— or —NR²⁷— (wherein R²³, R²⁴, R²⁵,    R²⁶ and R²⁷ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R²² represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is a 4-, 5- or 6-membered saturated heterocyclic    group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear 1    or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkanoyl, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonyl,    C₁₋₄akylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl,    C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl));-   6) C₁₋₅alkylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   7) C₂₋₅alkenylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   8) C₂₋₅alkenylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   9) R²⁹ (wherein R²⁹ represents a pyridone group, a phenyl group or a    5-6-membered aromatic heterocyclic group (linked via carbon or    nitrogen) with 1-3 heteroatoms selected from O, N and S, which    pyridone, phenyl or aromatic heterocyclic group may carry up to 5    substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,    C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR³⁰R³¹,    —NR³²C(O)R³³ (wherein R³⁰, R³¹ R³² and R³³, which may be the same or    different, each represents hydrogen, C₁₋₄alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD    (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or    6-membered saturated heterocyclic group with 1-2 heteroatoms,    selected independently from O, S and N, which cyclic group may bear    one or more substituents selected from C₁₋₄alkyl));-   10) C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) C₂₋₅alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   12) C₂₋₅akynylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   13) C₁₋₅alkylX⁶ R²⁹ (wherein X⁶represents —O—, —S—, —SO₂—, —SO₂—,    —NR³⁴C(O)—, —C(O)NR³⁵—, —SO₂NR³⁶, —NR³⁷SO₂— or —NR³⁸ — (wherein R³⁴,    R³⁵, R³⁶, R³⁷ and R³⁸ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   14) C₂₋₅alkenylX⁷R²⁹ (wherein X⁷ represents —O—, —S—, —SO—, —SO₂—,    —NR³⁹C(O)—, —C(O)N⁴⁰—, —SO₂NR⁴¹—, —NR⁴²SO₂— or —NR⁴³— (wherein R³⁹,    R⁴⁰, R⁴¹, R⁴² and R⁴³ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   15) C₂₋₅alkynylX⁸R²⁹ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—,    —NR⁴⁴C(O)—, —C(O)NR⁴⁵—, SO₂N⁴⁶—, —NR⁴⁷SO₂— or —NR⁴⁸ — (wherein R⁴⁴,    R⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   16) C₁₋₄alkylX⁹C₁₋₄alkylR²⁹ (wherein X⁹ represents —O—, —S—, —SO₂—,    —SO₂—, —NR⁴⁹C(O)—, —C(O)NR⁵⁰—, —SO₂NR⁵¹—, —NR⁵²SO₂— or —NR⁵³—    (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   17) C₁₋₄alkylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N-C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N-C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₅alkenylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   21) C₂₋₅alkynylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   22) C₁₋₄alkylR⁵⁴(C₁₋₄alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹ is as defined    hereinbefore, q is 0 or 1, r is 0 or 1, and R⁵⁴ and R⁵⁵ are each    independently selected from hydrogen, C₁₋₃alkyl, cyclopentyl,    cyclohexyl and a 4-, 5- or 6-membered saturated heterocyclic group    with 1-2 heteroatoms, selected independently from O, S and N, which    C₁₋₃alkyl group may bear 1 or 2 substituents selected from oxo,    hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group may bear 1    or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl), with the proviso that R⁵⁴ cannot be hydrogen);-   and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵X¹— may bear one or more substituents selected from    hydroxy, halogeno and amino);    or a salt thereof, or a prodrug thereof for example an ester or an    amide, in the manufacture of a medicament for use in the production    of an antiangiogenic and/or vascular permeability reducing effect in    warm-blooded animals such as humans.

According to another aspect of the present invention there is providedthe use of a compound of the formula I¹:

wherein:

-   Z is —O—, —NH—, —S—, —CH₂— or a direct bond; Z is linked to the benz    ring of the indole group at any of the positions 4-, 5-, 6- or 7- of    the indole group;-   n is an integer from 0 to 5; any of the substitutents R¹ maybe    attached at any free carbon atom of the indole group, such free    carbon atoms may be at positions 2-, 3-, 4-, 5-, 6-, or 7- of the    indole group;-   m is an integer from 0 to 3;-   R^(a) represents hydrogen;-   R^(b) represents hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,    aminoC₁₋₄alkyl, C₁₋₃alkylaminoC₁₋₄alkyl,    di(C₁₋₃alkyl)aminoC₁₋₄alkyl, —C₁₋₅alkyl(ring A) wherein ring A is    selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,    N-methylpiperazinyl, N-ethylpiperazinyl, morpholino and    thiomorpholino;-   R¹ represents hydrogen, oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, aminoC₁₋₄alkyl,    C₁₋₃alkylaminoC₁₋₄alkyl, di(C₁₋₃alkyl)aminoC₁₋₄alkyl,    —C₁₋₅alkyl(ring B) wherein ring B is selected from azetidinyl,    pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl,    N-ethylpiperazinyl, morpholino and thiomorpholino;-   R² represents hydrogen, hydroxy, halogeno, cyano, nitro,    trifluoromethyl, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylsulphanyl, —NR³R⁴    (wherein R³ and R⁴, which may be the same or different, each    represents hydrogen or C₁₋₃alkyl), or R⁵X¹— (wherein X¹ represents a    direct bond, —O—, —CH₂—, —OC(O)—, —C(O)—, —S—, —SO—, —SO₂—,    —NR⁶C(O)—, —C(O)NR⁷—, —SO₂NR⁷—, —NR⁹SO₂— or —NR¹⁰ (wherein R⁶, R⁷,    R⁸, R⁹ and R¹⁰ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl), and R⁵ is selected from one of the following    twenty-two groups:-   1) hydrogen, oxiranylC₁₋₄alkyl or C₁₋₅alkyl which maybe    unsubstituted or which may be substituted with one or more groups    selected from hydroxy, fluoro, chloro, bromo and amino;-   2) C₁₋₅alkylX²C(O)R¹¹ (wherein X² represents —O— or —NR¹²— (in which    R¹² represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹¹    represents C₁₋₃alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵    which may be the same or different each represents hydrogen,    C₁₋₅alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   3) C₁₋₅alkylX³R¹⁶ (wherein X³ represents —O—, —S—, —SO—, —SO₂—,    —OC(O)—, —NR¹⁷C(O)—, —C(O)NR¹⁸—, —SO₂NR¹⁹, —NR²⁰SO₂— or —N²¹—    (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ represents    hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 4-, 5- or    6-membered saturated heterocyclic group with 1-2 heteroatoms,    selected independently from O, S and N, which C₁₋₃alkyl group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and    C₁₋₄alkoxy and which cyclic group may bear 1 or 2 substituents    selected from oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl,    C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl));-   4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²² (wherein X⁴ and X⁵ which may be the    same or different are each —O—, —S—, —SO—, —SO₂—, —NR²³C(O)—,    —C(O)NR²⁴, —SO₂NR²⁵—, —NR²⁶SO₂— or —NR²⁷— (wherein R²³, R²⁴, R²⁵,    R²⁶ and R²⁷ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R²² represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is a 4-, 5- or 6-membered saturated heterocyclic    group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear 1    or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl));-   6) C₁₋₅alkylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   7) C₂₋₅alkenylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   8) C₂₋₅alkynylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   9) R²⁹ (wherein R²⁹ represents a pyridone group, a phenyl group or a    5-6-membered aromatic heterocyclic group (linked via carbon or    nitrogen) with 1-3 heteroatoms selected from O, N and S, which    pyridone, phenyl or aromatic heterocyclic group may carry up to 5    substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,    C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR³⁰R³¹,    NR³²C(O)R³³ (wherein R³⁰, R³¹, R³² and R³³, which may be the same or    different, each represents hydrogen, C₁₋₄alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD    (wherein f is 0 or 1, is 0 or 1 and ring D is a 4-, 5- or 6-membered    saturated heterocyclic group with 1-2 heteroatoms, selected    independently from O, S and N, which cyclic group may bear one or    more substituents selected from C₁₋₄alkyl));-   10) C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) C₂₋₅alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   12) C₂₋₅alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,    —N³⁴C(O)—, —C(O)NR³⁵—, SO₂NR³⁶—, —NR³⁷SO₂— or —NR³⁸— (wherein R³⁴,    R³⁵, R³⁶, R³⁷ and R³⁸ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   14) C₂₋₅alkenylX⁷R²⁹ (wherein X⁷ represents —O—, —S—, —SO—, —SO₂—,    —NR³⁹C(O)—, —C(O)NR⁴⁰—, —SO₂NR⁴¹—, —NR⁴²SO₂— or —NR⁴³— (wherein R³⁹,    R⁴⁰, R⁴¹, R⁴² and R⁴³ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   15) C₂₋₅alkynylX⁸R²⁹ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—,    —NR⁴⁴C(O)—, —C(O)N⁴⁵—, —SO₂NR⁴⁶—, —NR⁴⁷SO₂— or —NR⁴⁸ — (wherein R⁴⁴,    R⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   16) C₁₋₄alkylX⁹C₁₋₄alkylR²⁹ (wherein X⁹ represents —O—, —S—, —SO—,    —SO₂—, —NR⁴⁹C(O)—, —C(O)NR⁵⁰—, —SO₂NR⁵¹—, —NR⁵²SO₂— or —NR⁵³—    (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   17) C₁₋₄alkylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N-C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N-C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₅alkenylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   21) C₂₋₅alkynylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   22) C₁₋₄alkylR⁵⁴(C₁₋₄alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹ is as defined    hereinbefore, q is 0 or 1, r is 0 or 1, and R⁵⁴ and R⁵⁵ are each    independently selected from hydrogen, C₁₋₃alkyl, cyclopentyl,    cyclohexyl and a 4-, 5- or 6-membered saturated heterocyclic group    with 1-2 heteroatoms, selected independently from O, S and N, which    C₁₋₃alkyl group may bear 1 or 2 substituents selected from oxo,    hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group may bear 1    or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl), with the proviso that R⁵⁴ cannot be hydrogen);-   and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵X¹— may bear one or more substituents selected from    hydroxy, halogeno and amino);    or a salt thereof, or a prodrug thereof for example an ester or an    amide, in the manufacture of a medicament for use in the production    of an antiangiogenic and/or vascular permeability reducing effect in    warm-blooded animals such as humans.

Preferably Z is —O—, —NH—, —S— or a direct bond.

More preferably Z is —O—, —NH— or —S—.

Particularly Z is —O— or —NH—, especially —O—.

Preferably Z is linked to the indole, azaindole or indazole group at the5- or 6-positions of the indole, azaindole or indazole group.

More preferably Z is linked to the indole, azaindole or indazole groupat the 5-position of the indole, azaindole or indazole group.

Preferably Z is linked to an indole group at the 5- or 6-positions ofthe indole group.

More preferably Z is linked to an indole group at the 5-position of theindole group.

Preferably R^(b) represents hydrogen, C₁₋₂alkyl,C₂₋₃alkenylaminoC₂₋₃alkyl, C₂₋₃alkynylaminoC₂₋₃alkyl or —C₂₋₄alkyl(ringA) wherein ring A is selected from piperidinyl and piperazinyl andwherein ring A may bear one or more substituents selected fromC₁₋₂alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, hydroxy, cyano, cyanoC₁₋₂alkyl,C₁₋₂alkylsulphonyl and C₁₋₂alkanoyl.

More preferably R^(b) represents hydrogen, methyl,C₂₋₃alkenylaminoC₂₋₃alkyl, C₂₋₃alkynylaminoC₂₋₃alkyl or —C₂₋₃alkyl(ringA) wherein ring A is selected from 4-acetylpiperazin-1-yl,4-methylsulphonylpiperazin-1-yl, 4-cyanopiperazin-1-yl,4-cyanomethylpiperazin-1-yl, 4-(prop-2-en-1-yl)piperazin-1-yl,4-(prop-2-yn-1-yl)piperazin-1-yl and 4-hydroxypiperidino.

Particularly R^(b) is hydrogen or methyl, especially hydrogen.

Advantageously R¹ represents hydrogen, oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, aminoC₁₋₄alkyl,C₁₋₃alkylaminoC₁₋₄alkyl, di(C₁₋₃alkyl)aminoC₁₋₄alkyl, —C₁₋₅alkyl(ring B)wherein ring B is selected from azetidin-1-yl, pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, N-methylpiperazin-1-yl,N-ethylpiperazin-1-yl, morpholino and thiomorpholino.

Particularly R¹ represents methyl, ethyl, trifluoromethyl or halogeno.

Especially R¹ represents methyl, fluoro, chloro or bromo, moreespecially methyl or fluoro.

Preferably n is an integer from 0 to 3.

More preferably n is 0, 1 or 2.

According to one aspect of the present invention G₁ is nitrogen and G₂,G₃, G₄ and G₅ are —CH— forming an azaindole moiety which may bear one ormore substituents R¹ as defined hereinbefore.

According to another aspect of the present invention G₅ is nitrogen andG₁, G₂, G₃ and G₄ are —CH— forming an indazole moiety which may bear oneor more substituents R¹ as defined hereinbefore.

According to another aspect of the present invention G₁, G₂, G₃, G₄ andG₅ are all —CH— forming an indole moiety which may bear one or moresubstituents R¹ as defined hereinbefore.

In one embodiment of the invention the optionally substituted indole,azaindole or indazole moiety of formula II:

wherein R¹, R^(b), G₁, G₂, G₃, G₄ and G₅ and n are as definedhereinbefore; is selected from the indole moieties:

-   4-fluoro-2-methylindol-5-yl, 2-methylindol-5-yl, 2-methylindol-6-yl,    2,3-dimethylindol-5-yl, 1-methylindol-5-yl, 1,2-dimethylindol-5-yl,    4-fluoroindol-5-yl, 6-fluoroindol-5-yl and indol-5-yl,-   the azaindole moieties:-   1H-pyrrolo[2,3-b]pyridin-5-yl and    2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl,-   and the indazole moiety:-   1H-indazol-5-yl.    The indole moieties are preferred over the azaindole and indazole    moieties.

In another embodiment of the invention the optionally substituted indolemoiety of formula II¹:

wherein R¹, R^(b) and n are as defined hereinbefore;is selected from 4-fluoro-2-methylindol-5-yl, 2-methylindol-5-yl,2-methylindol-6-yl, 2,3-dimethylindol-5-yl, 1-methylindol-5-yl,1,2-dimethylindol-5-yl, 4-fluoroindol-5-yl, 6-fluoroindol-5-yl andindol-5-yl.

Particularly the optionally substituted indole moiety of formula II¹ isselected from 4-fluoro-2-methylindol-5-yl, 4-fluoroindol-5-yl and6-fluoroindol-5-yl, more especially from 4-fluoro-2-methylindol-5-yl.

Preferably m is an integer from 0 to 2, more preferably 1 or 2, mostpreferably 2.

Advantageously X¹ represents a direct bond, —O—, —S—, —NR⁶C(O)—,—NR⁹SO₂— or —NR¹⁰— (wherein R⁶, R⁹ and R¹⁰ each independently representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X¹ represents a direct bond, —O—, —S—, —NR⁶C(O)—, —NR⁹SO₂—(wherein R⁶ and R⁹ each independently represents hydrogen or C₁₋₂alkyl)or NH.

More preferably X¹ represents —O—, —S—, —NR⁶C(O)— (wherein R⁶ representshydrogen or C₁₋₂alkyl) or NH.

Particularly X¹ represents —O— or —NR⁶C(O)— (wherein R⁶ representshydrogen or C₁₋₂alkyl), more particularly —O— or —NHC(O)—, especially—O—.

According to another aspect of the present invention X¹ represents —O—or a direct bond.

Advantageously X² represents —O— or —NR¹² (wherein R¹² representshydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl).

Advantageously X³ represents —O—, —S—, —SO—, —SO₂—, —NR¹⁷C(O)—,—NR²⁰SO₂— or —NR²¹— (wherein R⁷, R²⁰ and R²¹ each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X³ represents —O—, —S—, —SO—, —SO₂— or —N²¹— (wherein R²¹represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

More preferably X³ represents —O— or —NR²¹— (wherein R²¹ representshydrogen or C₁₋₂alkyl).

According to another aspect of the present invention X³ represents —O—,—SO₂—, —NR²⁰SO₂— or —NR²¹— (wherein R²⁰ and R²¹ each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Advantageously X⁴ and X⁵ which may be the same or different eachrepresents —O—, —S—, —SO—, —SO₂— or —NR²⁷— (wherein R²⁷ representshydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl).

Preferably X⁴ and X⁵ which may be the same or different each represents—O—, —S— or —NR²⁷— (wherein R²⁷ represents hydrogen, C₁₋₂alkyl orC₁₋₂alkoxyethyl).

More preferably X⁴ and X⁵ which may be the same or different eachrepresents —O— or —NH—.

Especially X⁴ and X⁵ each represents —O—.

Advantageously X⁶ represents —O—, —S— or —NR³⁸— (wherein R³⁸ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X⁶ represents —O— or —NR³⁸— (wherein R³⁸ represents hydrogenor C₁₋₂alkyl).

Especially X⁶ represents —O—.

Advantageously X⁷ represents —O—, —S— or —NR⁴³— (wherein R⁴³ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X⁷ represents —O— or —NR⁴³— (wherein R⁴³ represents hydrogen,C₁₋₂alkyl).

Advantageously X⁸ represents —O—, —S— or —NR⁴⁸— (wherein R⁴⁸ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X⁸ represents —O— or —NR⁴⁸— (wherein R⁴⁸ represents hydrogenor C₁₋₂alkyl).

Advantageously X⁹ represents —O— or —NR⁵³— (wherein R⁵³ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X⁹ represents —O— or —NR⁵³— (wherein R⁵³ represents hydrogenor C₁₋₂alkyl).

Accordingly to another aspect of the present invention X⁹ represents—O—, —CONR⁵⁰— or —NR⁵³— (wherein R⁵⁰ and R⁵³ each independentlyrepresents hydrogen or C₁₋₂alkyl).

Conveniently R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl,imidazolidinyl, azetidinyl, morpholino or thiomorpholino which group maybear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃;alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino,di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl,azetidinyl, morpholino and thiomorpholino, which cyclic group may bearone or more substituents selected from C₁₋₃alkyl).

Advantageously R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl,azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl,morpholino and thiomorpholino).

In one embodiment of the present invention R²⁸ is pyrrolidinyl,piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino whichgroup may bear 1 or 2 substituents selected from a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

Particularly R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl,morpholino or thiomorpholino which group may bear 1 or 2 substituentsselected from oxo, hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl,C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl andC₁₋₂alkylsulphonylC₁₋₃alkyl.

According to another aspect of the present invention, preferably R²⁸ ispyrrolidinyl, piperazinyl, piperidinyl, morpholino or thiomorpholinowhich group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl and C₁₋₂alkylsulphonylC₁₋₃alkyl.

Where R²⁹ is a 5-6-membered aromatic heterocyclic group; it preferablyhas 1 or 2 heteroatoms, selected from O, N and S, of which morepreferably one is N, and may be substituted as hereinbefore defined.

R²⁹ is particularly a pyridone, phenyl, pyridyl, imidazolyl, thiazolyl,thienyl, triazolyl or pyridazinyl group which group may be substitutedas hereinbefore defined, more particularly a pyridone, pyridyl,imidazolyl, thiazolyl or triazolyl group, especially a pyridone,pyridyl, imidazolyl or triazolyl group which group may be substituted ashereinbefore defined.

In one embodiment of the invention R²⁹ represents a pyridone, phenyl or5-6-membered aromatic heterocyclic group with 1 to 3 heteroatomsselected from O, N and S, which group may preferably carry up to 2substituents, more preferably up to one substituent, selected from thegroup of substituents as hereinbefore defined.

In the definition of R²⁹, conveniently substituents are selected fromhalogeno, C₁₋₄alkyl, C₁₋₄alkoxy, cyano and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl,piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino,which cyclic group may bear one or more substituents selected fromC₁₋₃alkyl).

In the definition of R²⁹, more conveniently substituents are selectedfrom chloro, fluoro, methyl, ethyl and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

According to another embodiment of the present invention in thedefinition of R²⁹, conveniently substituents are selected from halogeno,C₁₋₄alkyl, C₁₋₄alkoxy and cyano, more conveniently substituents areselected from chloro, fluoro, methyl and ethyl.

Advantageously R⁵⁴ and R⁵⁵ are each independently a 4-, 5- or 6-memberedsaturated heterocyclic group with 1-2 heteroatoms, selectedindependently from O, S and N, which cyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl anda group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with1-2 heteroatoms, selected independently from O, S and N, which cyclicgroup may bear one or more substituents selected from C₁₋₃alkyl).

Preferably R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl, piperazinyl,piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholinowhich group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl , C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₃alkoxycarbonyl and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein fis 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected frompyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl,morpholino and thiomorpholino, which cyclic group may bear one or moresubstituents selected from C₁₋₃alkyl).

More preferably R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl,piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholinowhich group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₃alkoxycarbonyl and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein fis 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected frompyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

Particularly R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl,piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholinowhich group may bear 1 or 2 substituents selected from a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

More particularly R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl,piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholinowhich group is unsubstituted.

Conveniently R² represents hydroxy, halogeno, cyano, nitro,trifluoromethyl, C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is ashereinbefore defined and R⁵ is selected from one of the followingtwenty-two groups:

-   1) oxiranylC₁₋₄alkyl or C₁₋₅alkyl which may be unsubstituted or    which may be substituted with one or more groups selected from    fluoro, chloro and bromo, or C₂₋₅alkyl which may be unsubstituted or    substituted with one or more groups selected from hydroxy and amino;-   2) C₂₋₃alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹    represents C₁₋₃alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵    which may be the same or different are each C₁₋₄alkyl or    C₁₋₂alkoxyethyl));-   3) C₂₋₄alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶    represents hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 4-, 5-    or 6-membered saturated heterocyclic group with 1-2 heteroatoms,    selected independently from O, S and N, which C₁₋₃alkyl group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and    C₁₋₃alkoxy and which cyclic group may bear 1 or 2 substituents    selected from oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkylaminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl));-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   6) C₁₋₅alkylR⁵⁶ (wherein R⁵⁶ is a 4-, 5- or 6-membered saturated    heterocyclic group with 1-2 heteroatoms, selected independently from    O, S and N, which heterocyclic group is linked to C₁₋₅alkyl through    a carbon atom and which heterocyclic group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkanoyl, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl)) or C₂₋₅alkylR⁵⁷ (wherein R⁵⁷ is a 4-, 5- or 6-membered    saturated heterocyclic group with 1-2 heteroatoms, of which one is N    and the other may be selected independently from O, S and N, which    heterocyclic group is linked to C₂₋₅alkyl through a nitrogen atom    and which heterocyclic group may bear 1 or 2 substituents selected    from oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄alkylsulphonyl, C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl,    C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄ alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl));-   7) C₃₋₄alkenylR⁵⁸ (wherein R⁵⁸ represents R⁵⁶ or R⁵⁷ as defined    hereinbefore);-   8) C₃₋₄alkynylR⁵⁸ (wherein R⁵⁸ represents R⁵⁶ or R⁵⁷ as defined    hereinbefore);-   9) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   10) C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) C₃₋₅alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   12) C₃₋₅alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   14) C₄₋₅alkenylX⁷R²⁹ (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   15) C₄₋₅alkynylX⁸R²⁹ (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   16) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   17) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N-C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N-C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₅alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   21) C₂₋₅alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   22) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹, q, r, R⁵⁴    and R⁵⁵ are as defined hereinbefore);-   and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵X¹— may bear one or more substituents selected from    hydroxy, halogeno and amino].

Advantageously R² represents hydroxy, halogeno, cyano, nitro,trifluoromethyl, C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is ashereinbefore defined and R⁵ is selected from one of the followingtwenty-two groups:

-   1) C₁₋₄alkyl which may be unsubstituted or which may be substituted    with one or more groups selected from fluoro, chloro and bromo, or    C₂₋₅alkyl which may be unsubstituted or substituted with one or more    groups selected from hydroxy and amino;-   2) C₂₋₃alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹    represents —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be    the same or different are each C₁₋₄alkyl or C₁₋₂alkoxyethyl));-   3) C₂₋₄alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is    a group selected from C₁₋₃alkyl, cyclopentyl, cyclohexyl,    pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl    and tetrahydropyranyl, which C₁₋₃alkyl group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno and C₁₋₂alkoxy and    which cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl,    piperidinyl, imidazolidinyl, azetidinyl or tetrahydropyranyl group    may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,    cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,    C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,    C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,    C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)amino(C₁₋₃alkyl,    C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and    thiomorpholino, which cyclic group may bear one or more substituents    selected from C₁₋₃alkyl));-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   6) C₁₋₄alkylR⁵⁹ (wherein R⁵⁹ is a group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidin-1-yl, azetidinyl,    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and    1,3-dithian-2-yl, which group is linked to C₁₋₄alkyl through a    carbon atom and which group may bear 1 or 2 substituents selected    from oxo, hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl,    C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, C₁₋₂alkanoyl, C₁₋₂alkoxyC₁₋₃alkyl,    C₁₋₂alkylsulphonyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,    C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and    thiomorpholino, which cyclic group may bear one or more substituents    selected from C₁₋₃alkyl)) or C₂₋₄alkylR⁶⁰ (wherein R⁶⁰ is a group    selected from morpholino, thiomorpholino, azetidin-1-yl,    pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may bear    1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,    C₁₋₂alkanoyl, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonyl,    C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino,    di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and    thiomorpholino, which cyclic group may bear one or more substituents    selected from C₁₋₃alkyl));-   7) C₃₋₄alkenylR⁶¹ (wherein R⁶¹ represents R⁵⁹ or R⁶⁰ as defined    hereinbefore);-   8) C₃₋₄alkynylR⁶¹ (wherein R⁶¹ represents R⁵⁹ or R⁶⁰ as defined    hereinbefore);-   9) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   10) C₁₋₄alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) 1-R²⁹prop-1-en-3-yl or 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as    defined hereinbefore with the proviso that when R⁵ is    1-R²⁹prop-1-en-3-yl, R²⁹ is linked to the alkenyl group via a carbon    atom);-   12) 1-R²⁹prop-1-yl-3-yl or 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as    defined hereinbefore with the proviso that when R⁵ is    1-R²⁹prop-1-yn-3-yl, R²⁹ is linked to the alkynyl group via a carbon    atom);-   13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   14) 1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   15) 1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   16) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   17) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₄alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   21) C₂₋₄alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   22) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹, q, r, R⁵⁴    and R⁵⁵ are as defined hereinbefore);-   and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵X¹— may bear one or more substituents selected from    hydroxy, halogeno and amino].

Preferably R² represents hydroxy, halogeno, nitro, trifluoromethyl,C₁₋₃alkyl, cyano, amino or R⁵X¹— [wherein X¹ is as hereinbefore definedand R⁵ is selected from one of the following twenty groups:

-   1) C₁₋₃alkyl which may be unsubstituted or which may be substituted    with one or more groups selected from fluoro, chloro and bromo, or    C₂₋₃alkyl which may be unsubstituted or substituted with one or more    groups selected from hydroxy and amino;-   2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,    2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,    3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,    3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,    3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,    3-(carbamoyloxy)propyl, or    2-(N-methyl-N-(butoxycarbonyl)amino)ethyl;-   3) C₂₋₃alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is    a group selected from C₁₋₃alkyl, cyclopentyl, cyclohexyl,    pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl    and tetrahydropyranyl which group is linked to X³ through a carbon    atom and which C₁₋₃alkyl group may bear 1 or 2 substituents selected    from hydroxy, halogeno and C₁₋₂alkoxy and which cyclopentyl,    cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl,    imidazolidinyl or tetralhydropyranyl group may bear one substituent    selected from oxo, hydroxy, halogeno, cyano, C₁₋₂cyanoalkyl,    C₁₋₂alkyl, C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,    C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₂alkoxycarbonyl, C₁₋₃alkylamino,    di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    methylpiperazinyl, piperidinyl, azetidinyl, morpholino and    thiomorpholino));-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₂alkyl);-   5) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   6) C₁₋₃alkylR⁵⁹ (wherein R⁵⁹ is a group selected from pyrrolidinyl,    piperazinyl, piperidinyl, azetidinyl, imidazolidinyl,    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and    1,3-dithian-2-yl, which group is linked to C₁₋₃alkyl through a    carbon atom and which group may bear 1 or 2 substituents selected    from oxo, hydroxy, halogeno, cyano, C₁₋₂cyanoalkyl, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, C₁₋₂alkanoyl, C₁₋₂alkoxyC₁₋₃alkyl,    C₁₋₂alkylsulphonyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₂alkoxycarbonyl,    C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    methylpiperazinyl, piperidinyl, azetidinyl, morpholino and    thiomorpholino)) or C₂₋₃alkylR⁶⁰ (wherein R⁶⁰ is a group selected    from morpholino, thiomorpholino, azetidin- 1-yl, pyrrolidin-1-yl,    piperazin-1-yl and piperidino which group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₂cyanoalkyl, C₁₋₂alkyl, C₁₋₂hydroxyalkyl, C₁₋₂alkoxy,    C₁₋₂alkanoyl, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonyl,    C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₂alkoxycarbonyl, C₁₋₃alkylamino,    di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    methylpiperazinyl, piperidinyl, azetidinyl, morpholino and    thiomorpholino));-   7) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   8) C₁₋₄alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   9) 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined hereinbefore);-   10) 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined hereinbefore);-   11) C₁₋₃alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   12) 1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   13) 1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   14) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   15) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   16) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   17) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   18) C₂₋₃alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   19) C₂₋₃alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   20) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹, q, r, R⁵⁴    and R⁵⁵ are as defined hereinbefore);-   and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵X¹— may bear one or more substituents selected from    hydroxy, halogeno and amino].

More preferably R² represents hydroxy, C₁₋₃alkyl, amino or R⁵X¹—[wherein X¹ is as hereinbefore defined and R⁵ represents methyl, ethyl,benzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl,3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl,2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl,3-(N,N-diethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl,3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,2-(4-hydroxypiperidino)ethyl, 3-(4-hydroxypiperidino)propyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl,3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl,3-piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 3-pyridylmethyl, 2-(3-pyridyl)ethyl,3-(3-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,2-(4-cyanomethylpiperazin-1-yl)ethyl,3-(4-cyanomethylpiperazin-1-yl)propyl, 2-(4-acetylpiperazin-1-yl)ethyl,3-(4-acetylpiperazin-1-yl)propyl,2-(4-methylsulphonylpiperazin-1-yl)ethyl,3-(4-methylsulphonylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl,3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl,3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,morpholino, 2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,1-(2-pyrrolidinylethyl)piperidin-4-ylmethyl,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,1-(2-piperidinylethyl)piperidin-4-ylmethyl,1-(3-piperidinylpropyl)piperidin-4-ylmethyl,1-(2-morpholinoethyl)piperidin-4-ylmethyl,1-(3-morpholinopropyl)piperidin-4-ylmethyl,1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,1-(2-azetidinylethyl)piperidin-4-ylmethyl,1-(3-azetidinylpropyl)piperidin-4-ylmethyl,2-(1-(2-pyrrolidinylethyl)piperidin-4-yl)ethyl,2-(1-(3-pyrrolidinylpropyl)piperidin-4-yl)ethyl,2-(1-(2-piperidinylethyl)piperidin-4-yl)ethyl,2-(1-(3-piperidinylpropyl)piperidin-4-yl)ethyl,2-(1-(2-morpholinoethyl)piperidin-4-yl)ethyl,2-(1-(3-morpholinopropyl)piperidin-4-yl)ethyl,2-(1-(2-thiomorpholinoethyl)piperidin-4-yl)ethyl,2-(1-(3-thiomorpholinopropyl)piperidin-4-yl)ethyl,2-(1-(2-azetidinylethyl)piperidin-4-yl)ethyl,2-(1-(3-azetidinylpropyl)piperidin-4-yl)ethyl,3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,(2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl,3-pyrrolidin-1-yl-2-hydroxypropyl,(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2S)-3-(1-methylpiperazin-4-yl-2-hydroxypropyl,3-N,N-diethylamino)-2hydroxypropyl,(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or(2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].

Particularly R² represents C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is ashereinbefore defined and R⁵ represents ethyl, benzyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl,2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl,3-(N,N-diethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl,3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl,(1-methylpiperdin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,2-(4-hydroxypiperidino)ethyl, 3-(4-hydroxypiperidino)propyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl,2-(2-cyanomethylpiperidin-3-methylpiperidin-4-yl)propyl,3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl,3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 3-pyridylmethyl, 2-(3-pyridyl)ethyl,3-(3-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,2-(4-cyanomethylpiperazin-1-yl)ethyl,3-(4-cyanomethylpiperazin-1-yl)propyl, 2-(4-acetylpiperazin-1-yl)ethyl,3-(4-acetylpiperazin-1-yl)propyl,2-(4-methylsulphonylpiperazin-1-yl)ethyl,3-(4-methylsulphonylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl,3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl,3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,morpholino, 2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,1-(2-pyrrolidinylethyl)piperidin-4-ylmethyl,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,1-(2-piperidinylethyl)piperidin-4-ylmethyl,1-(3-piperidinylpropyl)piperidin-4-ylmethyl,1-(2-morpholinoethyl)piperidin-4-ylmethyl,1-(3-morpholinopropyl)piperidin-4-ylmethyl,1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,1-(2-azetidinylethyl)piperidin-4-ylmethyl,1-(3-azetidinylpropyl)piperidin-4-ylmethyl,2-(1-(2-pyrrolidinylethyl)piperidin-4-yl)ethyl,2-(1-(3-pyrrolidinylpropyl)piperidin-4-yl)ethyl,2-(1-(2-piperidinylethyl)piperidin-4-yl)ethyl,2-(1-(3-piperidinylpropyl)piperidin-4-yl)ethyl,2-(1-(2-morpholinoethyl)piperidin-4-yl)ethyl,2-(1-(3-morpholinopropyl)piperidin-4-yl)ethyl,2-(1-(2-thiomorpholinoethyl)piperidin-4-yl)ethyl,2-(1-(3-thiomorpholinopropyl)piperidin-4-yl)ethyl,2-(1-(2-azetidinylethyl)piperidin-4-yl)ethyl,2-(1-(3-azetidinylpropyl)piperidin-4-yl)ethyl,3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,(2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl,3-pyrrolidin-1-yl-2-hydroxypropyl,(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,3-(N,N-diethylamino)-2-hydroxypropyl,(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(isopropylamino)-2-hydroxypropyl,(2S)-3-(isopropylamino)-2-hydroxypropyl,3-(N,N-diisopropylamino)-2-hydroxypropyl,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or (2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].

More particularly R² represents C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ isas hereinbefore defined and R⁵ represents ethyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl,2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl,3-(N,N-diethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl,3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,2-(4-hydroxypiperidino)ethyl, 3-(4-hydroxypiperidino)propyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl,3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 3-pyridylmethyl, 2-(3-pyridyl)ethyl,3-(3-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,2-(4-cyanomethylpiperazin-1-yl)ethyl,3-(4-cyanomethylpiperazin-1-yl)propyl, 2-(4-acetylpiperazin-1-yl)ethyl,3-(4-acetylpiperazin-1-yl)propyl,2-(4-methylsulphonylpiperazin-1-yl)ethyl,3-(4-methylsulphonylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl,3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl,3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,morpholino, 2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,1-(2-pyrrolidinylethyl)piperidin-4-ylmethyl,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,1-(2-piperidinylethyl)piperidin-4-ylmethyl,1-(3-piperidinylpropyl)piperidin-4-ylmethyl,1-(2-morpholinoethyl)piperidin-4-ylmethyl,1-(3-morpholinopropyl)piperidin-4-ylmethyl,1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,1-(2-azetidinylethyl)piperidin-4-ylmethyl or1-(3-azetidinylpropyl)piperidin-4-ylmethyl,2-(1-(2-pyrrolidinylethyl)piperidin-4-yl)ethyl,2-(1-(3-pyrrolidinylpropyl)piperidin-4-yl)ethyl,2-(1-(2-piperidinylethyl)piperidin-4-yl)ethyl,2-(1-(3-piperidinylpropyl)piperidin-4-yl)ethyl,2-(1-(2-morpholinoethyl)piperidin-4-yl)ethyl,2-(1-(3-morpholinopropyl)piperidin-4-yl)ethyl,2-(1-(2-thiomorpholinoethyl)piperidin-4-yl)ethyl,2-(1-(3-thiomorpholinopropyl)piperidin-4-yl)ethyl;2-(1-(2-azetidinylethyl)piperidin-4-yl)ethyl,2-(1-(3-azetidinylpropyl)piperidin-4-yl)ethyl,3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,(2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl,3-pyrrolidin-1-yl-2-hydroxypropyl,(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,3-(N,N-diethylamino)-2-hydroxypropyl,(2R)-3-N,N-diethylamino)-2-hydroxypropyl,(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(isopropylamino)-2-hydroxypropyl,(2S)-3-(isopropylamino)-2-hydroxypropyl,3-(N,N-diisopropylamino)-2-hydroxypropyl,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or(2S)-3-(N,N-diisopropylamino)-2hydroxypropyl].

In another aspect R² represents ethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,2-methoxyethoxy, 3-methoxypropoxy, 2-(methylsulphinyl)ethoxy,2-(methylsulphonyl)ethoxy, 2-(ethylsulphinyl)ethoxy,2-(ethylsulphonyl)ethoxy, 2-N,N-dimethylsulphamoyl)ethoxy,2-(N-methylsulphamoyl)ethoxy, 2-sulphamoylethoxy, 2-(methylamino)ethoxy,3-(methylamino)propoxy, 2-(ethylamino)ethoxy, 3-(ethylamino)propoxy,2-(N,N-dimethylamino)ethoxy, 3-(N,N-dimethylamino)propoxy,2-(N,N-diethylamino)ethoxy, 3-(N,N-diethylamino)propoxy,2-(N-methyl-N-methylsulphonylamino)ethoxy,3-(N-methyl-N-methylsulphonylamino)propoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-(methylpiperidino)ethoxy, 3-(methylpiperidino)propoxy,2-(ethylpiperidino)ethoxy, 3-(ethylpiperidino)propoxy,2-((2-methoxyethyl)piperidino)ethoxy,3-((2-methoxyethyl)piperidino)propoxy,2-((2-methylsulphonyl)ethylpiperidino)ethoxy,3-((2-methylsulphonyl)ethylpiperidino)propoxy, piperidin-3-ylmethoxy,piperidin-4-ylmethoxy, 2-(piperidin-3-yl)ethoxy,2-(piperidin-4-yl)ethoxy, 3-(piperidin-3-yl)propoxy,3-(piperidin-4-yl)propoxy, 2-piperidin-2-yl)ethoxy,3-(piperidin-2-yl)propoxy, (1-methylpiperidin-3-yl)methoxy,(1-methylpiperidin-4-yl)methoxy, 2-(4-hydroxypiperidino)ethoxy,3-(4-hydroxypiperidino)propoxy, (1-cyanomethylpiperidin-3-yl)methoxy,(1-cyanomethylpiperidin-4-yl)methoxy, 2-(methylpiperidin-3-yl)ethoxy,2-(methylpiperidin-4-yl)ethoxy, 2-(1-cyanomethylpiperidin-3-yl)ethoxy,2-(1-cyanomethylpiperidin-4-yl)ethoxy, 3-(methylpiperidin-3-yl)propoxy,3-(methylpiperidin-4-yl)propoxy, 3-(1-cyanomethylpiperidin-3-yl)propoxy,3-(1-cyanomethylpiperidin-4-yl)propoxy, 2-(ethylpiperidin-3-yl)ethoxy,2-(ethylpiperidin-4-yl)ethoxy, 3-(ethylpiperidin-3-yl)propoxy,3-(ethylpiperidin-4-yl)propoxy, ((2-methoxyethyl)piperidin-3-yl)methoxy,((2-methoxyethyl)piperidin-4-yl)methoxy,2-((2-methoxyethyl)piperidin-3-yl)ethoxy,2-((2-methoxyethyl)piperidin-4-yl)ethoxy,3-((2-methoxyethyl)piperidin-3-yl)propoxy,3-((2-methoxyethyl)piperidin-4-yl)propoxy,(1-(2-methylsulphonylethyl)piperidin-3-yl)methoxy,(1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy,2-((2-methylsulphonylethyl)piperidin-3-yl)ethoxy,2-((2-methylsulphonylethyl)piperidin-4-yl)ethoxy,3-((2-methylsulphonylethyl)piperidin-3-yl)propoxy,3-((2-methylsulphonylethyl)piperidin-4-yl)propoxy,1-isopropylpiperidin-2-ylmethoxy, 1-isopropylpiperidin-3-ylmethoxy,1-isopropylpiperidin-4-ylmethoxy, 2-(1-isopropylpiperidin-2-yl)ethoxy,2-(1-isopropylpiperidin-3-yl)ethoxy,2-(1-isopropylpiperidin-4-yl)ethoxy,3-(1-isopropylpiperidin-2-yl)propoxy,3-(1-isopropylpiperidin-3-yl)propoxy,3-(1-isopropylpiperidin-4-yl)propoxy, 2-(piperidin-4-yloxy)ethoxy,3-(piperidin-4-yloxy)propoxy,2-(1-(cyanomethyl)piperidin-4-yloxy)ethoxy,3-(1-(cyanomethyl)piperidin-4-yloxy)propoxy,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propoxy, 2-(piperazin-1-yl)ethoxy,3-(piperazin-1-yl)propoxy, (pyrrolidin-2-yl)methoxy,2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,(1,3-dioxolan-2-yl)methoxy, 2-(1,3-dioxolan-2-yl)ethoxy,2-(2-methoxyethylamino)ethoxy,2-(N-(2-methoxyethyl)-N-methylamino)ethoxy,2-(2-hydroxyethylamino)ethoxy, 3-(2-methoxyethylamino)propoxy,3-(N-(2-methoxyethyl)-N-methylamino)propoxy,3-(2-hydroxyethylamino)propoxy, 2-(1,2,3-triazol-1-yl)ethoxy,2-(1,2,3-triazol-2-yl)ethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,2-(1,2,4-triazol-4-yl)ethoxy, 4-pyridylmethoxy, 2-(4-pyridyl)ethoxy,3-(4-pyridyl)propoxy, 3-pyridylmethoxy, 2-(3-pyridyl)ethoxy,3-(3-pyridyl)propoxy, 2-(4-pyridyloxy)ethoxy, 2-(4-pyridylamino)ethoxy,2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy,2-(2-oxo-imidazolidin-1-yl)ethoxy, 3-(2-oxo-imidazolidin-1-yl)propoxy,2-thiomorpholinoethoxy, 3-thiomorpholinopropoxy,2-(1,1-dioxothiomorpholino)ethoxy, 3-(1,1-dioxothiomorpholino)propoxy,2-(2-methoxyethoxy)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-(4-acetylpiperazin-1-yl)ethoxy, 3-(4-acetylpiperazin-1-yl)propoxy,2-(4-methylsulphonylpiperazin-1-yl)ethoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy, 3-(methylsulphinyl)propoxy,3-(methylsulphonyl)propoxy, 3-(ethylsulphinyl)propoxy,3-(ethylsulphonyl)propoxy, 2-(5-methyl-1,2,4-triazol-1-yl)ethoxy,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethoxy,2-((N-methyl-N-4-pyridyl)amino)ethoxy, 3-(4-oxidomorpholino)propoxy,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy,3-(2-(4-methylpiperazin-1-yl)ethoxy)propoxy,2-(2-morpholinoethoxy)ethoxy, 3-(2-morpholinoethoxy)propoxy,2-(tetrahydropyran-4-yloxy)ethoxy, 3-(tetrahydropyran-4-yloxy)propoxy,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yloxy,1-(2-pyrrolidinylethyl)piperidin-4-ylmethoxy,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyoxy,1-(2-piperidinylethyl)piperidin-4-ylmethoxy,1-(3-piperidinylpropyl)piperidin-4-ylmethoxy,1-(2-morpholinoethyl)piperidin-4-ylmethoxy,1-(3-morpholinopropyl)piperidin-4-ylmethoxy,1-(2-thiomorpholinoethyl)piperidin-4-ylmethoxy,1-(3-thiomorpholinopropyl)piperidin-4-ylmethoxy,1-(2-azetidinylethyl)piperidin-4-ylmethoxy,1-(3-azetidinylpropyl)piperidin-4-ylmethoxy,2-(1-(2-pyrrolidinylethyl)piperidin-4-yl)ethoxy,2-(1-(3-pyrrolidinylpropyl)piperidin-4-yl)ethoxy,2-(1-(2-piperidinylethyl)piperidin-4-yl)ethoxy,2-(1-(3-piperidinylpropyl)piperidin-4-yl)ethoxy,2-(1-(2-morpholinoethyl)piperidin-4-yl)ethoxy,2-(1-(3-morpholinopropyl)piperidin-4-yl)ethoxy,2-(1-(2-thiomorpholinoethyl)piperidin-4-yl)ethoxy,2-(1-(3-thiomorpholinopropyl)piperidin-4-yl)ethoxy,2-(1-(2-azetidinylethyl)piperidin-4-yl)ethoxy,2-(1-(3-azetidinylpropyl)piperidin-4-yl)ethoxy,3-morpholino-2-hydroxypropoxy, (2R)-3-morpholino-2-hydroxypropoxy,(2S)-3-morpholino-2-hydroxypropoxy, 3-piperidino-2-hydroxypropoxy,(2R)-3-piperidino-2-hydroxypropoxy, (2S)-3-piperidino-2-hydroxypropoxy,3-pyrrolidin-1-yl-2-hydroxypropoxy,(2R)-3-pyrrolidin-1-yl-2-hydroxypropoxy,(2S)-3-pyrrolidin-1-yl-2-hydroxypropoxy,3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,3-(N,N-diethylamino)-2-hydroxypropoxy,(2R)-3-(N,N-diethylamino)-2-hydroxypropoxy,(2S)-3-(N,N-diethylamino)-2-hydroxypropoxy,3-(isopropylamino)-2-hydroxypropoxy,(2R)-3-(isopropylamino)-2-hydroxypropoxy,(2S)-3-(isopropylamino)-2-hydroxypropoxy,3-(N,N-diisopropylamino)-2-hydroxypropoxy,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropoxy or(2S)-3-(N,N-diisopropylamino)-2-hydroxypropoxy.

According to another aspect of the present invention conveniently R²represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, C₁₋₃alkyl,amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selectedfrom one of the following twenty-two groups:

-   1) oxiranylC₁₋₄alkyl or C₁₋₅alkyl which may be unsubstituted or    which may be substituted with one or more groups selected from    fluoro, chloro and bromo, or C₂₋₅alkyl which may be unsubstituted or    substituted with one or more groups selected from hydroxy and amino;-   2) C₂₋₃alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹    represents C₁₋₃alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵    which may be the same or different are each C₁₋₄alkyl or    C₁₋₂alkoxyethyl));-   3) C₂₋₄alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶    represents hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 4-, 5-    or 6-membered saturated heterocyclic group with 1-2 heteroatoms,    selected independently from O, S and N, which C₁₋₃alkyl group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and    C₁₋₃alkoxy and which cyclic group may bear 1 or 2 substituents    selected from oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl));-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   6) C₁₋₅alkylR⁵⁶ (wherein R⁵⁶ is a 4-, 5- or 6-membered saturated    heterocyclic group with 1-2 heteroatoms, selected independently from    O, S and N, which heterocyclic group is linked to C₁₋₅alkyl through    a carbon atom and which heterocyclic group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,    C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,    C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl)) or C₂₋₅alkylR⁵⁷ (wherein R⁵⁷ is a 4-, 5- or 6-membered    saturated heterocyclic group with 1-2 heteroatoms, of which one is N    and the other may be selected independently from O, S and N, which    heterocyclic group is linked to C₂₋₅alkyl through a nitrogen atom    and which heterocyclic group may bear 1 or 2 substituents selected    from oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄akylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4-, 5- or 6-membered saturated heterocyclic group with    1-2 heteroatoms, selected independently from O, S and N, which    cyclic group may bear one or more substituents selected from    C₁₋₄alkyl));-   7) C₃₋₄alkenylR⁵⁸ (wherein R⁵⁸ represents R⁵⁶ or R⁵⁷ as defined    hereinbefore);-   8) C₃₋₄alkynylR⁵⁸ (wherein R⁵⁸ represents R⁵⁶ or R⁵⁷ as defined    hereinbefore);-   9) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   10) C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) C₃₋₅alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   12) C₃₋₅alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   14) C₄₋₅alkenylX⁷R²⁹ (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   15) C₄₋₅alkynylX⁸R²⁹ (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   16) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   17) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N-C₁₋₄alkylaminosulplhonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N-C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₅alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   21) C₂₋₅alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   22) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)^(r)R⁵⁵ (wherein X⁹, q, r, R⁵⁴    and R⁵⁵ are as defined hereinbefore);-   and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵X¹— may bear one or more substituents selected from    hydroxy, halogeno and amino].

According to another aspect of the present invention advantageously R²represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, C₁₋₃alkyl,amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selectedfrom one of the following twenty-two groups:

-   1) C₁₋₄alkyl which may be unsubstituted or which may be substituted    with one or more groups selected from fluoro, chloro and bromo, or    C₂₋₅alkyl which may be unsubstituted or substituted with one or more    groups selected from hydroxy and amino;-   2) C₂₋₃alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹    represents —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be    the same or different are each C₁₋₄alkyl or C₁₋₂alkoxyethyl));-   3) C₂₋₄alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is    a group selected from C₁₋₃alkyl, cyclopentyl, cyclohexyl,    pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl    and tetrahydropyranyl, which C₁₋₃alkyl group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno and C₁₋₂alkoxy and    which cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl,    piperidinyl, imidazolidinyl, azetidinyl or tetrahydropyranyl group    may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,    cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,    C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,    C₁₋₃alloxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,    C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,    C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and    thiomorpholino, which cyclic group may bear one or more substituents    selected from C₁₋₃alkyl));-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   6) C₁₋₄alkylR⁵⁹ (wherein R⁵⁹ is a group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidin-1-yl, azetidinyl,    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and    1,3-dithian-2-yl, which group is linked to C₁₋₄alkyl through a    carbon atom and which group may bear 1 or 2 substituents selected    from oxo, hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl,    C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,    C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino,    di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and    thiomorpholino, which cyclic group may bear one or more substituents    selected from C₁₋₃alkyl)) or C₂₋₄alkylR⁶⁰ (wherein R⁶⁰ is a group    selected from morpholino, thiomorpholino, azetidin-1-yl,    pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may bear    1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,    C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,    C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino, di(C₃alkyl)amino,    C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,    C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and    thiomorpholino, which cyclic group may bear one or more substituents    selected from C₁₋₃alkyl));-   7) C₃₋₄alkenylR⁶¹ (wherein R⁶¹ represents R⁵⁹ or R⁶⁰ as defined    hereinbefore);-   8) C₃₋₄alkynylR⁶¹ (wherein R⁶¹ represents R⁵⁹ or R⁶⁰ as defined    hereinbefore);-   9) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   10) C₁₋₄alkylR²⁹ (wherein R²⁹is as defined hereinbefore);-   11) 1-R²⁹prop-1-en-3-yl or 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as    defined hereinbefore with the proviso that when R⁵ is    1-R²⁹prop-1-en-3-yl, R²⁹ is linked to the alkenyl group via a carbon    atom);-   12) 1-R²⁹prop-1-yn-3-yl or 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as    defined hereinbefore with the proviso that when R⁵ is    1-R²⁹prop-1-yn-3-yl, R²⁹ is linked to the alkynyl group via a carbon    atom);-   13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   14) 1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   15) 1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   16) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   17) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₄alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   21) C₂₋₄alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   22) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹, q, r, R⁵⁴    and R⁵⁵ are as defined hereinbefore);-   and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵X¹— may bear one or more substituents selected from    hydroxy, halogeno and amino].

According to another aspect of the present invention preferably R²represents hydroxy, halogeno, nitro, trifluoromethyl, C₁₋₃alkyl, cyano,amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selectedfrom one of the following twenty groups:

-   1) C₁₋₃alkyl which may be unsubstituted or which may be substituted    with one or more groups selected from fluoro, chloro and bromo, or    C₂₋₃alkyl which may be unsubstituted or substituted with one or more    groups selected from hydroxy and amino;-   2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,    2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,    3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,    3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,    3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,    3-(carbamoyloxy)propyl, or    2-(N-methyl-N-(butoxycarbonyl)amino)ethyl;-   3) C₂₋₃alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is    a group selected from C₁₋₃alkyl, cyclopentyl, cyclohexyl,    pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl    and tetrahydropyranyl which group is linked to X³ through a carbon    atom and which C₁₋₃alkyl group may bear 1 or 2 substituents selected    from hydroxy, halogeno and C₁₋₂alkoxy and which cyclopentyl,    cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl,    imidazolidinyl or tetrahydropyranyl group may bear one substituent    selected from oxo, hydroxy, halogeno, cyano, C₁₋₂cyanoalkyl,    C₁₋₂alkyl, C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,    C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₂alkoxycarbonyl, C₁₋₃alkylamino,    di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    methylpiperazinyl, piperidinyl, azetidinyl, morpholino and    thiomorpholino));-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₂alkyl),-   5) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   6) C₁₋₃alkylR⁵⁹ (wherein R⁵⁹ is a group selected from pyrrolidinyl,    piperazinyl, piperidinyl, azetidinyl, imidazolidinyl,    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and    1,3-dithian-2-yl, which group is linked to C₁₋₃alkyl through a    carbon atom and which group may bear 1 or 2 substituents selected    from oxo, hydroxy, halogeno, cyano, C₁₋₂cyanoalkyl, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,    C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₂alkoxycarbonyl, C₁₋₃alkylamino,    di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or -1, g is 0 or 1    and ring D is a heterocyclic group selected from pyrrolidinyl,    methylpiperazinyl, piperidinyl, azetidinyl, morpholino and    thiomorpholino)) or C₂₋₃alkylR⁶⁰ (wherein R⁶⁰ is a group selected    from morpholino, thiomorpholino, azetidin-1-yl, pyrrolidin-1-yl,    piperazin-1-yl and piperidino which group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₂cyanoalkyl, C₁₋₂alkyl, C₁₋₂hydroxyalkyl, C₁₋₂alkoxy,    C₁₋₂alkoxyC₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₂alkoxycarbonyl,    C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    methylpiperazinyl, piperidinyl, azetidinyl, morpholino and    thiomorpholino));-   7) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   8) C₁₋₄alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   9) 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined hereinbefore);-   10) 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined hereinbefore);-   11) C₁₋₃alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   12) 1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   13) 1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   14) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   15) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   16) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulplhonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   17) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl    and N,N-di(C₄alkyl)aminosulphonyl;-   18) C₂₋₃alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   19) C₂₋₃alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   20) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹, q, r, R⁵⁴    and R⁵⁵ are as defined hereinbefore);-   and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵X¹— may bear one or more substituents selected from    hydroxy, halogeno and amino].

According to another aspect of the present invention more preferably R²represents hydroxy, C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is ashereinbefore defined and R⁵ represents methyl, ethyl, benzyl,trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl,2-(ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(methylamino)ethyl,3-(methylamino)propyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl,2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,2-(N,N-diethylamino)ethyl, 3-(N,N-diethylamino)propyl,2-(N-methyl-N-methylsulphonylamino)ethyl,3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl,3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl,3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl,2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino,2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,1-(2-pyrrolidinylethyl)piperidin-4-ylmethyl,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,1-(2-piperidinylethyl)piperidin-4-ylmethyl;1-(3-piperidinylpropyl)piperidin-4-ylmethyl,1-(2-morpholinoethyl)piperidin-4-ylmethyl,1-(3-morpholinopropyl)piperidin-4-ylmethyl,1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,1-(2-azetidinylethyl)piperidin-4-ylmethyl or1-(3-azetidinylpropyl)piperidin-4-ylmethyl,3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,(2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl,3-pyrrolidin-1-yl-2-hydroxypropyl,(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,3-(N,N-diethylamino)-2-hydroxypropyl,(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(isopropylamino)-2-hydroxypropyl,(2S)-3-(isopropylamino)-2-hydroxypropyl,3-(N,N-diisopropylamino)-2-hydroxypropyl,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or(2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].

According to another aspect of the present invention particularly R²represents C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is as hereinbeforedefined and R⁵ represents ethyl, benzyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl,2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl,3-(N,N-diethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl,3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl,3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl,3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl,2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino,2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,1-(2-pyrrolidinylethyl)piperidin-4-ylmethyl,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,1-(2-piperidinylethyl)piperidin-4-ylmethyl,1-(3-piperidinylpropyl)piperidin-4-ylmethyl,1-(2-morpholinoethyl)piperidin-4-ylmethyl,1-(3-morpholinopropyl)piperidin-4-ylmethyl,1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,1-(2-azetidinylethyl)piperidin-4-ylmethyl or1-(3-azetidinylpropyl)piperidin-4-ylmethyl,3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,(2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl,3-pyrrolidin-1-yl-2-hydroxypropyl, (2R)-3-pyrrolidin1-yl-2-hydroxypropyl, (2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,3-(N,N-diethylamino)-2-hydroxypropyl,(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(isopropylamino)-2-hydroxypropyl,(2S)-3-(isopropylamino)-2-hydroxypropyl,3-(N,N-diisopropylamino)-2-hydroxypropyl,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or(2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].

According to another aspect of the present invention more particularlyR² represents C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is as hereinbeforedefined and R⁵ represents ethyl, trifluoromethyl, 2,2,2-trifluoroethyl,2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl,2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl,3-(N,N-diethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl,3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl,3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl,3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl,2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,1-(2-pyrrolidinylethyl)piperidin-4-ylmethyl,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,1-(2-piperidinylethyl)piperidin-4-ylmethyl,1-(3-piperidinylpropyl)piperidin-4-ylmethyl,1-(2-morpholinoethyl)piperidin-4-ylmethyl,1-(3-morpholinopropyl)piperidin-4-ylmethyl,1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,1-(2-azetidinylethyl)piperidin-4-ylmethyl or1-(3-azetidinylpropyl)piperidin-4-ylmethyl,3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,(2R)-3-piperidino-2-hydroxypropyl, (2R)-3-piperidino-2-hydroxypropyl,3-pyrrolidin-1-yl-2-hydroxypropyl,(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,3-(N,N-diethylamino)-2-hydroxypropyl,(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(isopropylamino)-2-hydroxypropyl,(2S)-3-(isopropylamino)-2-hydroxypropyl,3-(N,N-diisopropylamino)-2-hydroxypropyl,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or(2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].

In another aspect R² represents ethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,2-methoxyethoxy, 3-methoxypropoxy, 2-(methylsulphinyl)ethoxy,2-(methylsulphonyl)ethoxy, 2-(ethylsulphinyl)ethoxy,2-(ethylsulphonyl)ethoxy, 2-(N,N-dimethylsulphamoyl)ethoxy,2-(4-methylsulphamoyl)ethoxy, 2-sulphamoylethoxy, 2-(methylamino)ethoxy,3-(methylamino)propoxy, 2-(ethylamino)ethoxy, 3-(ethylamino)propoxy,2-(N,N-dimethylamino)ethoxy, 3-(N,N-dimethylamino)propoxy,2-(N,N-diethylamino)ethoxy, 3-(N,N-diethylamino)propoxy,2-(N-methyl-N-methylsulphonylamino)ethoxy,3-(N-methyl-N-methylsulphonylamino)propoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-(methylpiperidino)ethoxy, 3-(methylpiperidino)propoxy,2-(ethylpiperidino)ethoxy, 3-(ethylpiperidino)propoxy,2-((2-methoxyethyl)piperidino)ethoxy,3-((2-methoxyethyl)piperidino)propoxy,2-((2-methylsulphonyl)ethylpiperidino)ethoxy,3-((2-methylsulphonyl)ethylpiperidino)propoxy, piperidin-3-ylmethoxy,piperidin-4-ylmethoxy, 2-(piperidin-3-yl)ethoxy,2-(piperidin-4-yl)ethoxy, 3-(piperidin-3-yl)propoxy,3-(piperidin-4-yl)propoxy, 2-(piperidin-2-yl)ethoxy,3-(piperidin-2-yl)propoxy, (1-methylpiperidin-3-yl)methoxy,(1-methylpiperidin-4-yl)methoxy, (1-cyanomethylpiperidin-3-yl)methoxy,(1-cyanomethylpiperidin-4-yl)methoxy, 2-(methylpiperidin-3-yl)ethoxy,2-(methylpiperidin-4-yl)ethoxy, 2-(1-cyanomethylpiperidin-3-yl)ethoxy,2-(1-cyanomethylpiperidin-4-yl)ethoxy, 3-(methylpiperidin-3-yl)propoxy,3-(methylpiperidin-4-yl)propoxy, 3-(1-cyanomethylpiperidin-3-yl)propoxy,3-(1-cyanomethylpiperidin-4-yl)propoxy, 2-(ethylpiperidin-3-yl)ethoxy,2-(ethylpiperidin-4-yl)ethoxy, 3-(ethylpiperidin-3-yl)propoxy,3-(ethylpiperidin-4-yl)propoxy, ((2-methoxyethyl)piperidin-3-yl)methoxy,((2-methoxyethyl)piperidin-4-yl)methoxy,2-((2-methoxyethyl)piperidin-3-yl)ethoxy,2-((2-methoxyethyl)piperidin-4-yl)ethoxy,3-((2-methoxyethyl)piperidin-3-yl)propoxy,3-((2-methoxyethyl)piperidin-4-yl)propoxy,(1-(2-methylsulphonylethyl)piperidin-3-yl)methoxy,(1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy,2-((2-methylsulphonylethyl)piperidin-3-yl)ethoxy,2-((2-methylsulphonylethyl)piperidin-4-yl)ethoxy,3-((2-methylsulphonylethyl)piperidin-3-yl)propoxy,3-((2-methylsulphonylethyl)piperidin-4-yl)propoxy,1-isopropylpiperidin-2-ylmethoxy, 1-isopropylpiperidin-3-ylmethoxy,1-isopropylpiperidin-4-ylmethoxy, 2-(1-isopropylpiperidin-2-yl)ethoxy,2-(1-isopropylpiperidin-3-yl)ethoxy,2-(1-isopropylpiperidin-4-yl)ethoxy,3-(1-isopropylpiperidin-2-yl)propoxy,3-(1-isopropylpiperidin-3-yl)propoxy,3-(1-isopropylpiperidin-4-yl)propoxy, 2-(piperidin-4-yloxy)ethoxy,3-(piperidin-4-yloxy)propoxy,2-(1-(cyanomethyl)piperidin-4-yloxy)ethoxy,3-(1-(cyanomethyl)piperidin-4-yloxy)propoxy,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propoxy, 2-(piperazin-1-yl)ethoxy,3-(piperazin-1-yl)propoxy, (pyrrolidin-2-yl)methoxy,2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,(1,3-dioxolan-2-yl)methoxy, 2-(1,3-dioxolan-2-yl)ethoxy,2-(2-methoxyethylamino)ethoxy,2-(N-(2-methoxyethyl)-N-methylamino)ethoxy,2-(2-hydroxyethylamino)ethoxy, 3-(2-methoxyethylamino)propoxy,3-(N-(2-methoxyethyl)-N-methylamino)propoxy,3-(2-hydroxyethylamino)propoxy, 2-(1,2,3-triazol-1-yl)ethoxy,2-(1,2,3-triazol-2-yl)ethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,2-(1,2,4-triazol-4-yl)ethoxy, 4-pyridylmethoxy, 2-(4-pyridyl)ethoxy,3-(4-pyridyl)propoxy, 2-(4-pyridyloxy)ethoxy, 2-(4-pyridylamino)ethoxy,2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy,2-(2-oxo-imidazolidin-1-yl)ethoxy, 3-(2-oxo-imidazolidin-1-yl)propoxy,2-thiomorpholinoethoxy, 3-thiomorpholinopropoxy,2-(1,1-dioxothiomorpholino)ethoxy, 3-(1,1-dioxothiomorpholino)propoxy,2-(2-methoxyethoxy)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(methylsulphinyl)propoxy,3-(methylsulphonyl)propoxy, 3-(ethylsulphinyl)propoxy,3-(ethylsulphonyl)propoxy, 2-(5-methyl-1,2,4-triazol-1-yl)ethoxy,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethoxy,2-((N-methyl-N-4-pyridyl)amino)ethoxy, 3-(4-oxidomorpholino)propoxy,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy,3-(2-(4-methylpiperazin-1-yl)ethoxy)propoxy,2-(2-morpholinoethoxy)ethoxy, 3-(2-morpholinoethoxy)propoxy,2-(tetrahydropyran-4-yloxy)ethoxy, 3-(tetrahydropyran-4-yloxy)propoxy,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yloxy,1-(2-pyrrolidinylethyl)piperidin-4-ylmethoxy,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethoxy,1-(2-piperidinylethyl)piperidin-4-ylmethoxy,1-(3-piperidinylpropyl)piperidin-4-ylmethoxy,1-(2-morpholinoethyl)piperidin-4-ylmethoxy,1-(3-morpholinopropyl)piperidin-4-ylmethoxy,1-(2-thiomorpholinoethyl)piperidin-4-ylmethoxy,1-(3-thiomorpholinopropyl)piperidin-4-ylmethoxy,1-(2-azetidinylethyl)piperidin-4-ylmethoxy,1-(3-azetidinylpropyl)piperidin-4-ylmethoxy,3-morpholino-2-hydroxypropoxy, (2R)-3-morpholino-2-hydroxypropoxy,(2S)-3-morpholino-2-hydroxypropoxy, 3-piperidino-2-hydroxypropoxy,(2R)-3-piperidino-2-hydroxypropoxy, (2S)-3-piperidino-2-hydroxypropoxy,3-pyrrolidin-1-yl-2-hydroxypropoxy,(2R)-3-pyrrolidin-1-yl-2-hydroxypropoxy,(2S)-3-pyrrolidin-1-yl-2-hydroxypropoxy,3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy, (2,S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,3-(N,N-diethylamino)-2-hydroxypropoxy,(2R)-3-(N,N-diethylamino)-2-hydroxypropoxy,(2S)-3-(N,N-diethylamino)-2-hydroxypropoxy,3-(isopropylamino)-2-hydroxypropoxy,(2R)-3-(isopropylamino)-2-hydroxypropoxy,(2S)-3-(isopropylamino)-2-hydroxypropoxy,3-(N,N-diisopropylamino)-2-hydroxypropoxy,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropoxy or(2S)-3-(N,N-diisopropylamino)-2-hydroxypropoxy.

Where one of the R² substituents is R⁵X¹— the substituent R⁵X¹— ispreferably at the 5- or 7-position of the cinnoline ring, morepreferably at the 7-position of the cinnoline ring.

When one of the R² substituents is at the 6-position of the cinnolinering it is preferably hydrogen, halogeno, C₁₋₃alkyl, trifluoromethyl,cyano, C₁₋₃alkoxy, C₁₋₃alkylsulphanyl or —NR³R⁴ (wherein R³ and R⁴ areas defined hereinbefore).

When one of the R² substituents is at the 6-position of the cinnolinering it is more preferably hydrogen, C₁₋₃alkoxy, cyano, trifluoromethyl,C₁₋₃alkylsulphanyl, fluoro, chloro, bromo or nitro.

When one of the R² substituents is at the 6-position of the cinnolinering it is particularly hydrogen, methoxy or cyano.

When one of the R² substituents is at the 6-position of the cinnolinering it is especially methoxy.

In another aspect of the present invention there is provided the use ofcompounds of the formula Ia:

wherein

-   R^(a), R^(b), R¹, R², n and m are as defined hereinbefore and Za    represents —O—, —NH— or —S—;    or a salt thereof, or a prodrug thereof for example an ester or an    amide, in the manufacture of a medicament for use in the production    of an antiangiogenic and/or vascular permeability reducing effect in    warm-blooded animals such as humans.

In a further aspect of the present invention there is provided the useof compounds of the formula Ib:

wherein R^(a), R^(b), R¹, R², n and m are as defined hereinbefore and Zbrepresents —O— or —NH—;or a salt thereof, or a prodrug thereof for example an ester or anamide, in the manufacture of a medicament for use in the production ofan antiangiogenic and/or vascular permeability reducing effect inwarm-blooded animals such as humans.

In a further aspect of the present invention there is provided the useof compounds of the formula Ib as defined hereinbefore, with the provisothat R² at the 7-position of the cinnoline ring cannot have any valueselected from hydrogen, methyl, methoxy and chloro; or a salt thereof,or a prodrug thereof for example an ester or an amide, in themanufacture of a medicament for use in the production of anantiangiogenic and/or vascular permeability reducing effect inwarm-blooded animals such as humans.

According to another aspect of the present invention there is provided acompound of the formula I as defined hereinbefore and salts thereof, andprodrugs thereof for example esters, amides and sulphides, preferablyesters and amides.

According to another aspect of the present invention there is provided acompound of the formula I¹ as defined hereinbefore and salts thereof,and prodrugs thereof for example esters, amides and sulphides,preferably esters and amides.

According to another aspect of the present invention there is provided acompound of the formula Ia as defined hereinbefore and salts thereof,and prodrugs thereof for example esters, amides and sulphides,preferably esters and amides.

According to another aspect of the present invention there is provided acompound of the formula Ib as defined hereinbefore and salts thereof,and prodrugs thereof for example esters, amides and sulphides,preferably esters and amides.

According to another aspect of the present invention there is provided acompound of the formula Ib as defined hereinbefore with the proviso thatR² at the 7-position of the cinnoline ring cannot have any valueselected from hydrogen, methyl, methoxy and chloro; and salts thereof,and prodrugs thereof for example esters, anodes and sulphides,preferably esters and amides.

Preferred compounds of the present invention include

-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline,-   7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-7-(R)-(2-hydroxy-3-(piperidin-1-yl)propoxy)-6-methoxycinnoline,    and-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(piperidin-4-ylmethoxy)cinnoline,    and salts thereof.

More preferred compounds of the present invention include

-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(piperidin-4-ylmethoxy)cinnoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-7-(R)-(2-hydroxy-3-(piperidin-1-yl)propoxy)-6-methoxycinnoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)cinnoline,-   7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-7-(R)-(2-hydroxy-3-pyrrolidin-1-yl)propoxy)-6-methoxycinnoline,-   4-(4-fluoro-2-methylindol-5-yl)oxy-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)cinnoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)cinnoline,    and salts thereof.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’ the said group encompasses the first occurring andbroadest definition as well as each and all of the preferred definitionsfor that group.

In this specification unless stated otherwise the term “alkyl” includesboth straight and branched chain alkyl groups but references toindividual alkyl groups such as “propyl” are specific for the straightchain version only. An analogous convention applies to other genericterms. Unless otherwise stated the term “alkyl” advantageously refers tochains with 1-6 carbon atoms, preferably 1-4 carbon atoms. The term“alkoxy” as used herein, unless stated otherwise includes “alkyl” —O—groups in which “alkyl” is as hereinbefore defined. The term “aryl” asused herein unless stated otherwise includes reference to a C₆₋₁₀ arylgroup which may, if desired, carry one or more substituents selectedfrom halogeno, alkyl, alkoxy, nitro, trifluoromethyl and cyano, (whereinalkyl and alkoxy are as hereinbefore defined). The term “aryloxy” asused herein unless otherwise stated includes “aryl” —O— groups in which“aryl” is as hereinbefore defined. The term “sulphonyloxy” as usedherein refers to alkylsulphonyloxy and arylsulphonyloxy groups in which“alkyl” and “aryl” are as hereinbefore defined. The term “alkanoyl” asused herein unless otherwise stated includes formyl and alkylC═O groupsin which “alkyl” is as defined hereinbefore, for example C₂alkanoyl isethanoyl and refers to CH₃C═O, C₁alkanoyl is formyl and refers to CHO.In this specification unless stated otherwise the term “alkenyl”includes both straight and branched chain alkenyl groups but referencesto individual alkenyl groups such as 2-butenyl are specific for thestraight chain version only. Unless otherwise stated the term “alkenyl”advantageously refers to chains with 2-5 carbon atoms, preferably 3-4carbon atoms. In this specification unless stated otherwise the term“alkynyl” includes both straight and branched chain alkynyl groups butreferences to individual alkynyl groups such as 2-butynyl are specificfor the straight chain version only. Unless otherwise stated the term“alkynyl” advantageously refers to chains with 2-5 carbon atoms,preferably 3-4 carbon atoms. Unless stated otherwise the term“haloalkyl” refers to an alkyl group as defined hereinbefore which bearsone or more halogeno groups, such as for example trifluoromethyl.

For the avoidance of any doubt, where R² has a value of substituted orunsubstituted C₁₋₅alkyl, R² has been selected from C₁₋₃alkyl or from agroup R⁵X¹ wherein X¹ is a direct bond or —CH₂— and R⁵ is C₁₋₅alkylwhich may be unsubstituted or which may be substituted with one or moregroups selected from hydroxy, fluoro, chloro, bromo and amino.

Within the present invention it is to be understood that a compound ofthe formula I or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form whichinhibits VEGF receptor tyrosine kinase activity and is not to be limitedmerely to any one tautomeric form utilised within the formulae drawings.The formulae drawings within this specification can represent only oneof the possible tautomeric forms and it is to be understood that thespecification encompasses all possible tautomeric forms of the compoundsdrawn not just those forms which it has been possible to showgraphically herein.

It will be appreciated that compounds of the formula I or a salt thereofmay possess an asymmetric carbon atom. Such an asymmetric carbon atom isalso involved in the tautomerism described above, and it is to beunderstood that the present invention encompasses any chiral form(including both pure enantiomers, scalemic and racemic mixtures) as wellas any tautomeric form which inhibits VEGF receptor tyrosine kinaseactivity, and is not to be limited merely to any one tautomeric form orchiral form utilised within the formulae drawings. It is to beunderstood that the invention encompasses all optical and diastereomerswhich inhibit VEGF receptor tyrosine kinase activity. It is further tobe understood that in the names of chiral compounds (R,S) denotes anyscalemic or racemic mixture while (R) and (S) denote the enantiomers. Inthe absence of (R,S), (R) or (S) in the name it is to be understood thatthe name refers to any scalemic or racemic mixture, wherein a scalemicmixture contains R and S enantiomers in any relative proportions and aracemic mixture contains R and S enantiomers in the ration 50:50.

It is also to be understood that certain compounds of the formula I andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which inhibit VEGF receptor tyrosinekinase activity.

For the avoidance of any doubt, it is to be understood that when X¹ is,for example, a group of formula —NR⁶C(O)—, it is the nitrogen atombearing the R⁶ group which is attached to the cinnoline ring and thecarbonyl (C(O)) group is attached to R⁵, whereas when X¹ is, forexample, a group of formula —C(O)NR⁷—, it is the carbonyl group which isattached to the cinnoline ring and the nitrogen atom bearing the R⁷group is attached to R⁵. A similar convention applies to the other twoatom X¹ linking groups such as —NR⁹SO₂— and —SO₂NR⁸—. When X¹ is —NR¹⁰—it is the nitrogen atom bearing the R¹⁰ group which is linked to thecinnoline ring and to R⁵. An analogous convention applies to othergroups. It is further to be understood that when X¹ represents —NR¹⁰—and R¹⁰ is C₁₋₃alkoxyC₂₋₃alkyl it is the C₂₋₃alkyl moiety which islinked to the nitrogen atom of X¹ and an analogous convention applies toother groups.

For the avoidance of any doubt, it is to be understood that in acompound of the formula I when R⁵ is, for example, a group of formulaC₁₋₃alkylX⁹C₁₋₃alkylR²⁹, it is the terminal C₁₋₃alkyl moiety which islinked to X¹, similarly when R⁵ is, for example, a group of formulaC₂₋₅alkenylR²⁸ it is the C₂₋₅alkenyl moiety which is linked to X¹ and ananalogous convention applies to other groups. When R⁵ is a group1-R²⁹prop-1-en-3-yl it is the first carbon to which the group R²⁹ isattached and it is the third carbon which is linked to X¹ and ananalogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that in acompound of the formula I when R⁵ is, for example, R²⁸ and R²⁸ is apyrrolidinyl ring which bears a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD, itis the —O— or C₁₋₄alkyl which is linked to the pyrrolidinyl ring, unlessf and g are both 0 when it is ring D which is linked to the pyrrolidinylring and an analogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that when R²⁹carries a C₁₋₄aminoalkyl substituent it is the C₁₋₄alkyl moiety which isattached to R²⁹ whereas when R²⁹ carries a C₁₋₄alkylamino substituent itis the amino moiety which is attached to R²⁹ and an analogous conventionapplies to other groups.

For the avoidance of any doubt, it is to be understood that when R²⁸carries a C₁₋₄alkoxyC₁₋₄alkyl substituent it is the C₁₋₄alkyl moietywhich is attached to R²⁸ and an analogous convention applies to othergroups.

For the avoidance of any doubt, it is to be understood that when R¹ is—C₁₋₅alkyl(ring B) it is the alkyl chain which is linked to the indolegroup and ring B is attached to the alkyl chain and an analogousconvention applies to other groups.

For the avoidance of any doubt, it is to be understood that when R^(b)is C₂₋₅alkenylaminoC₁₋₄alkyl, it is the C₁₋₄alkyl group which is linkedto the nitrogen atom of the 5-membered ring and an analogous conventionapplies to other groups.

The present invention relates to the compounds of formula I ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula I and their pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts of the invention may, for example, include acidaddition salts of the compounds of formula I as hereinbefore definedwhich are sufficiently basic to form such salts. Such acid additionsalts include for example salts with inorganic or organic acidsaffording pharmaceutically acceptable anions such as with hydrogenhalides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid. Inaddition where the compounds of formula I are sufficiently acidic,pharmaceutically acceptable salts may be formed with an inorganic ororganic base which affords a pharmaceutically acceptable cation. Suchsalts with inorganic or organic bases include for example an alkalimetal salt, such as a sodium or potassium salt, an alkaline earth metalsalt such as a calcium or magnesium salt, an ammonium salt or forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

A compound of the formula I, or salt thereof, and other compounds of theinvention (as hereinafter defined) may be prepared by any process knownto be applicable to the preparation of chemically-related compounds.Such processes include, for example, those illustrated in InternationalPatent Application Publication No. WO 97/34876 and in InternationalPatent Application Publication No. WO 00/47212 (Application No.PCT/GB00/00373). Such processes also include, for example, solid phasesynthesis. Such processes, are provided as a further feature of theinvention and are as described hereinafter. Necessary starting materialsmay be obtained by standard procedures of organic chemistry. Thepreparation of such starting materials is described within theaccompanying non-limiting Examples. Alternatively necessary startingmaterials are obtainable by analogous procedures to those illustratedwhich are within the ordinary skill of an organic chemist.

Thus, the following processes (a) to (f) and (i) to (vi) constitutefurther features of the present invention.

Synthesis of Compounds of Formula I

(a) Compounds of the formula I and salts thereof may be prepared by thereaction of a compound of the formula III:

(wherein R^(a), R² and m are as defined hereinbefore and L¹ is adisplaceable moiety), with a compound of the formula IV:

(wherein R^(b), R¹, G₁, G₂, G₃, G₄, G₅, Z and n are as definedhereinbefore) to obtain compounds of the formula I and salts thereof. Aconvenient displaceable moiety L¹ is, for example, a halogeno, alkoxy(preferably C₁₋₄alkoxy), aryloxy, alkylsulphanyl, arylsulphanyl,alkoxyalkylsulphanyl or sulphonyloxy group, for example a chloro, bromo,methoxy, phenoxy, methylsulphanyl, 2-methoxyethylsulphanyl,methanesulphonyloxy or toluene-4-sulphonyloxy group.

The reaction is advantageously effected in the presence of a base. WhenZ is —O— such a base is, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine or for example, analkali metal or alkaline earth metal carbonate or hydroxide, for examplesodium carbonate, potassium carbonate, cesium carbonate, calciumcarbonate, sodium hydroxide or potassium hydroxide. Alternatively such abase is, for example, an alkali metal hydride, for example sodiumhydride, or an alkali metal or alkaline earth metal amide, for examplesodium amide, sodium bis(trimethylsilyl)amide, potassium amide orpotassium bis(trimethylsilyl)amide. The reaction is preferably effectedin the presence of an inert solvent or diluent, for example an ethersuch as tetrahydrofuran or 1,4-dioxan, an aromatic hydrocarbon solventsuch as toluene, or a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneor dimethyl sulphoxide. The reaction is conveniently effected at atemperature in the range, for example, 10 to 150° C., preferably in therange 20 to 110° C.

When Z is —NH— the reaction is advantageously effected in the presenceof either an acid or a base. Such an acid is for example, an anhydrousinorganic acid such as hydrochloric acid, in the presence of a proticsolvent or diluent, for example an alcohol or ester such as methanol,ethanol, 2-propanol, 2-pentanol.

When it is desired to obtain the acid salt, the free base may be treatedwith an acid such as a hydrogen halide, for example hydrogen chloride,sulphuric acid, a sulphonic acid, for example methane sulphonic acid, ora carboxylic acid, for example acetic or citric acid, using aconventional procedure.

(b) Production of those compounds of formula I and salts thereof whereinat least one R² is R⁵X¹ wherein R⁵ is as defined hereinbefore and X¹ is—O—, —S—, —OC(O)— or —NR¹⁰— (wherein R¹⁰ independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) can be achieved by thereaction, conveniently in the presence of a base (as definedhereinbefore in process (a)) of a compound of the formula V:

(wherein R^(a), R^(b), Z, G₁, G₂, G₃, G₄, G₅, R¹, R² and n are ashereinbefore defined and X¹ is as hereinbefore defined in this sectionand s is an integer from 0 to 2) with a compound of formula VI:R⁵-L¹  (VI)(wherein R⁵ and L¹ are as hereinbefore defined), L¹ is a displaceablemoiety for example a halogeno or sulphonyloxy group such as a bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group, or L¹ may begenerated in situ from an alcohol under standard Mitsunobu conditions(“Organic Reactions”, John Wiley & Sons Inc, 1992, vol 42, chapter 2,David L Hughes). The reaction is preferably effected in the presence ofa base (as defined hereinbefore in process (a)) and advantageously inthe presence of an inert solvent or diluent (as defined hereinbefore inprocess (a)), advantageously at a temperature in the range, for example10 to 150° C., conveniently at about 50° C.

(c) Compounds of the formula I and salts thereof wherein at least one R²is R⁵X¹ wherein R⁵ is as defined hereinbefore and X¹ is —O—, —S—,—OC(O)— or —NR¹⁰— (wherein R¹⁰ represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) may be prepared by the reaction of a compound ofthe formula VII:

with a compound of the formula VIII:R⁵—X¹—H  (VIII)(wherein L¹, R^(a), R^(b), R¹, R², R⁵, G₁, G₂, G₃, G₄, G₅, Z, n and sare all as hereinbefore defined and X¹ is as hereinbefore defined inthis section). The reaction may conveniently be effected in the presenceof a base (as defined hereinbefore in process (a)) and advantageously inthe presence of an inert solvent or diluent (as defined hereinbefore inprocess (a)), advantageously at a temperature in the range, for example10 to 150° C., conveniently at about 100° C.

(d) Compounds of the formula I and salts thereof wherein at least one R²is R⁵X¹ wherein X¹ is as defined hereinbefore and R⁵ is C₁₋₅alkylR⁶²,wherein R⁶² is selected from one of the following nine groups:

-   1) X¹⁰C₁₋₃alkyl (wherein X¹⁰ represents —O—, —S—, —SO₂—, —NR⁶³C(O)—    or —NR⁶⁴SO₂— (wherein R⁶³ and R⁶⁴ which maybe the same or different    are each hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl);-   2) NR⁶⁵R⁶⁶ (wherein R⁶⁵ and R⁶⁶ which may be the same or different    are each hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl);-   3) X¹¹C₁₋₅alkylX⁵R²² (wherein X¹¹ represents —O—, —S—, —SO₂—,    —NR⁶⁷C(O)—, —NR⁶⁸SO₂— or —NR⁶⁹ (wherein R⁶⁷, R⁶⁸, and R⁶⁹ which may    be the same or different are each hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and X⁵ and R²² are as defined hereinbefore);-   4) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   5) X¹²R²⁹ (wherein X¹² represents —O—, —S—, —SO₂—, —NR⁷⁰C(O)—,    —NR⁷¹SO₂—, or —NR⁷²— (wherein R⁷⁰, R⁷¹, and R⁷² which may be the    same or different are each hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined hereinbefore); and-   6) X¹³C₁₋₃alkylR²⁹ (wherein X¹³ represents —O—, —S—, —SO₂—,    —NR⁷³C(O)—, —NR⁷⁴SO₂— or —NR⁷⁵— (wherein R⁷³, R⁷⁴ and R⁷⁵ each    independently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)    and R²⁹ is as defined hereinbefore);-   7) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   8) X¹³C₁₋₄alkylR²⁸ (wherein X¹³ and R²⁸ are as defined    hereinbefore); and-   9) R⁵⁴(C₁₋₄alkyl)_(q)(X⁹)^(r)R⁵⁵ (wherein q, r, X⁹, R⁵⁴ and R⁵⁵ are    as defined hereinbefore); may be prepared by reacting a compound of    the formula IX:    (wherein L¹, X¹, R^(a), R^(b), R¹, R², G₁, G₂, G₃, G₄, G₅, Z, n and    s are as hereinbefore defined) with a compound of the formula X:    R⁶²—H  (X)    (wherein R⁶² is as defined hereinbefore) to give a compound of the    formula I or salt thereof. The reaction may conveniently be effected    in the presence of a base (as defined hereinbefore in process (a))    and advantageously in the presence of an inert solvent or diluent    (as defined hereinbefore in process (a)), and at a temperature in    the range, for example 0 to 150° C., conveniently at about 50° C.

Processes (a) and (b) are preferred over processes (c) and (d).

Process (a) is preferred over processes (b), (c) and (d).

(e) The production of those compounds of the formula I and salts thereofwherein one or more of the substituents (R²)_(m) is represented by—NR⁷⁶R⁷⁷ where one (and the other is hydrogen) or both of R⁷⁶ and R⁷⁷are C₁₋₃alkyl, may be effected by the reaction of compounds of formula Iwherein the substituent (R²)_(m) is an amino group and an alkylatingagent, preferably in the presence of a base as defined hereinbefore.Such alkylating agents are C₁₋₃alkyl moieties bearing a displaceablemoiety as defined hereinbefore such as C₁₋₃alkyl halides for exampleC₁₋₃alkyl chloride, bromide or iodide. The reaction is preferablyeffected in the presence of an inert solvent or diluent (as definedhereinbefore in process (a)) and at a temperature in the range, forexample, 10 to 100° C., conveniently at about ambient temperature. Theproduction of compounds of formula I and salts thereof wherein one ormore of the substituents R² is an amino group may be effected by thereduction of a corresponding compound of formula I wherein thesubstituent(s) at the corresponding position(s) of the cinnoline groupis/are a nitro group(s). The reduction may conveniently be effected asdescribed in process (i) hereinafter. The production of a compound offormula I and salts thereof wherein the substituent(s) at thecorresponding position(s) of the cinnoline group is/are a nitro group(s)maybe effected by the processes described hereinbefore and hereinafterin processes (a-d) and (i-v) using a compound selected from thecompounds of the formulae (I-XXII) in which the substituent(s) at thecorresponding position(s) of the cinnoline group is/are a nitrogroup(s).

(f) Compounds of the formula I and salts thereof wherein X¹ is —SO— or—SO₂— may be prepared by oxidation from the corresponding compound inwhich X¹ is —S— or —SO— (when X¹ is —SO₂— is required in the finalproduct). Conventional oxidation conditions and reagents for suchreactions are well known to the skilled chemist.

Synthesis of Intermediates

(i) The compounds of formula III and salts thereof in which L¹ ishalogeno may for example be prepared by halogenating a compound of theformula XI:

wherein R¹, R² and m are as hereinbefore defined).

Convenient halogenating agents include inorganic acid halides, forexample thionyl chloride, phosphorus(III)chloride,phosphorus(V)oxychloride and phosphorus(V)chloride. The halogenationreaction may be effected in the presence of an inert solvent or diluentsuch as for example a halogenated solvent such as methylene chloride,trichloromethane or carbon tetrachloride, or an aromatic hydrocarbonsolvent such as benzene or toluene, or the reaction may be effectedwithout the presence of a solvent. The reaction is conveniently effectedat a temperature in the range, for example 10 to 150° C., preferably inthe range 40 to 100° C.

The compounds of formula XI and salts thereof may, for example, beprepared by reacting a compound of the formula XII:

(wherein R^(a), R², s and L¹ are as hereinbefore defined) with acompound of the formula VIII as hereinbefore defined. The reaction mayconveniently be effected in the presence of a base (as definedhereinbefore in process (a)) and advantageously in the presence of aninert solvent or diluent (as defined hereinbefore in process (a)),advantageously at a temperature in the range, for example 10 to 150° C.,conveniently at about 110° C.

The compounds of formula XI and salts thereof may also be prepared bycyclising a compound of the formula XIII:

(wherein R² and m are as hereinbefore defined) whereby to form acompound of formula XI or salt thereof. The cyclisation may beconveniently effected in the presence of a mineral or organic acid, forexample sulphuric acid, hydrochloric acid or acetic acid or a mixturethereof, preferably at a temperature in the range 20° C. to 100° C.,especially 50-80° C. or if desired under pH-controlled conditions,advantageously at a pH of 4.0 to 8.5. Preferably the pH of the solutionis maintained within the range of 6.5 to 8.0. The desired pH isconveniently obtained by the use of an inert base or by the use of anaqueous solution of such a base. Bases which may be used include alkalimetal bicarbonates, carbonates or hydroxides or organic amines such asfor example pyridine or tertiary amines such as triethylamine,diisopropylethylamine, 2,6-lutidine, collidine, 4-dimethylaminopyridineor methylmorpholine [for example as described in U.S. Pat. No. 4,620,000(L. R. Denes) or DD 258809 (Hirsch et al.)]

The compounds of formula XIII and salts thereof, may for example beprepared by diazotisation of a compound of the formula XV:

(wherein R² and m are as hereinbefore defined). The diazotisation isconveniently effected by the use of an alkali metal nitrite, such assodium nitrite, in the presence of a mineral acid such as hydrochloricor sulphuric acid or in the presence of an organic acid such as aceticacid or in the presence of a mixture of such acids. The diazotisation isadvantageously effected at a temperature in the range between thefreezing point of the reaction mixture and 20° C., preferably from 0 to20° C.

Preferably the compounds of formula XI are prepared by diazotisation andin situ cyclisation of the resulting compound of formula XIII forexample as described by Borsch W. and Herbert A. Annalen der Chemie,Volume 546, p293-303.

Compounds of formula XIV and salts thereof, may for example be preparedby reduction of the nitro group in a compound of formula XV:

(wherein R² and m are as hereinbefore defined) to yield a compound offormula XIV as hereinbefore defined or salt thereof. The reduction ofthe nitrogroup may conveniently be effected by any of the proceduresknown for such a transformation. The reduction may be carried out, forexample, by the hydrogenation of a solution of the nitro compound in thepresence of an inert solvent or diluent as defined hereinbefore in thepresence of a metal effective to catalyse hydrogenation reactions suchas palladium or platinum. A further reducing agent is, for example, anactivated metal such as activated iron (produced for example by washingiron powder with a dilute solution of an acid such as hydrochloricacid). Thus, for example, the reduction may be effected by heating thenitro compound and the activated metal in the presence of a solvent ordiluent such as a mixture of water and alcohol, for example methanol orethanol, to a temperature in the range, for example 50 to 150° C.,conveniently at about 70° C.

Where the reduction is effected in the presence of activated iron, thisis advantageously produced in situ, conveniently by the use of iron,generally iron powder, in the presence of acetic acid/water andpreferably at about 100° C.

The compounds of formula XV and salts thereof may for example beproduced by reacting a compound of formula XVI:

(wherein R², s and L¹ are as hereinbefore defined) with a compound offormula VIII as hereinbefore defined to yield a compound of formula XVas hereinbefore defined or salt thereof. The reaction of the compoundsof formula XVI and VIII is conveniently effected under conditions asdescribed for process (c) hereinbefore.

Compounds of formula XVI and salts thereof may for example be preparedby nitration of a compound of the formula XVII:

(wherein R², s and L¹ are as hereinbefore defined) whereby to form acompound of formula XVII as hereinbefore defined or a salt thereof. Thenitration is conveniently effected in the presence of nitric acid whichmay be dilute or concentrated, but is preferably about 70% nitric acid.The nitration is conveniently effected at a temperature in the range 0to 20° C. The nitration may also be effected in the presence of a Lewisacid catalyst such as tin(IV)chloride. Where a Lewis acid catalyst isused the reaction is advantageously effected at a lower temperature,conveniently in the range −50 to 0° C., preferably at about −30° C.,preferably in the presence of methylene chloride.

The compounds of formula XV, as defined hereinbefore, and salts thereofmay for example be prepared by nitration of compounds of the formulaXVII in which the L¹ moiety is replaced by R². The nitration isconveniently effected as described hereinbefore.

The compounds of formula XII, as defined hereinbefore, and salts thereofmay for example be prepared from compounds of the formulae XIII and XIV,in which the R² group(s) is/are replaced by the moiety L¹, the reactionsmay be effected by processes as described above for the preparation ofcompounds of formula XI from compounds of formulae XIII and XIV.Compounds of the formula XIV in which the R² group is replaced by themoiety L¹ may be prepared by the reduction of the nitro group incompounds of the formula XVI, the reduction may be effected as definedhereinbefore.

The compounds of formula III and salts thereof wherein at least one R²is R⁵X¹ and wherein X¹ is —O—, —S—, —SO₂—, —OC(O)—, —C(O)NR⁷—, —SO₂NR⁸—or —NR¹⁰— (wherein R⁷, R⁸ and R¹⁰ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), may also be prepared forexample by reacting a compound of the formula XVIII:

(wherein R^(a), R² and s are as hereinbefore defined, X¹ is ashereinbefore defined in this section and L² represents a displaceableprotecting moiety) with a compound of the formula VI as hereinbeforedefined, whereby to obtain a compound of formula III in which L¹ isrepresented by L².

A compound of formula XVIII is conveniently used in which L² representsa chloro group or a phenoxy group which may if desired carry up to 5substituents, preferably up to 2 substituents, selected from halogeno,nitro and cyano. The reaction may be conveniently effected underconditions as described for process (b) hereinbefore.

The compounds of formula XVIII and salts thereof may for example beprepared by deprotecting a compound of the formula XIX:

(wherein R^(a), R², s and L² are as hereinbefore defined, P¹ is aprotecting group and X¹ is as hereinbefore defined in the sectiondescribing compounds of the formula XVIII). The choice of protectinggroup P¹ is within the standard knowledge of an organic chemist, forexample those included in standard texts such as “Protective Groups inOrganic Synthesis” T. W. Greene and R. G. M. Wuts, 2nd Ed. Wiley 1991,including N-sulphonyl derivatives (for example, p-toluenesulphonyl),carbamates (for example, t-butyl carbonyl), N-alkyl derivatives (forexample, 2-chloroethyl, benzyl) and amino acetal derivatives (forexample benzyloxymethyl). The removal of such a protecting group may beeffected by any of the procedures known for such a transformation,including those reaction conditions indicated in standard texts such asthat indicated hereinbefore, or by a related procedure. Deprotection maybe effected by techniques well known in the literature, for examplewhere P¹ represents a benzyl group deprotection may be effected byhydrogenolysis or by treatment with trifluoroacetic acid.

One compound of formula III may if desired be converted into anothercompound of formula III in which the moiety L¹ is different. Thus forexample a compound of formula III in which L¹ is other than halogeno,for example optionally substituted phenoxy, may be converted to acompound of formula III in which L¹ is halogeno by hydrolysis of acompound of formula III (in which L¹ is other than halogeno) to yield acompound of formula XI as hereinbefore defined, followed by introductionof halide to the compound of formula XI, thus obtained as hereinbeforedefined, to yield a compound of formula II in which L¹ representshalogen.

(ii) Compounds of formula IV may be prepared by any of the methods knownin the art, such as for example those described in “Indoles Part I”,“Indoles Part II”, 1972 John Wiley & Sons Ltd and “Indoles Part III”1979, John Wiley & Sons Ltd, edited by W. J. Houlihan. Compounds offormula IV may be prepared by any of the methods described in theExamples hereinafter.

Compounds of formula IV may be prepared by any of the processesdescribed in International Patent Application Publication No. WO00/47212, the entire content of which is included herein by reference,with particular reference to the processes described in WO 00/47212 inExamples 48, 182 237, 242, 250 and 291 therein.

For example the azaindole 2-methyl-1H-pyrrolo[2,3-b]pyridin-5-ol, may beprepared according to the method described in Reference Example 1hereinafter.

(iii) Compounds of formula V as hereinbefore defined and salts thereofmay be made by deprotecting the compound of formula XX:

(wherein R^(a), R^(b), Z, R¹, R², G₁, G₂, G₃, G₄, G₅, P¹, n and s are ashereinbefore defined and X¹ is as hereinbefore defined in the sectiondescribing compounds of the formula V) by a process for example asdescribed in (i) above.

Compounds of the formula XX and salts thereof may be made by reactingcompounds of the formulae XIX and IV as hereinbefore defined, under theconditions described in (a) hereinbefore, to give a compound of theformula XX or salt thereof.

(iv) Compounds of the formula VII and salts thereof may be made byreacting a compound of the formula XXI:

(wherein R^(a), R², s and each L¹ are as hereinbefore defined and the L¹in the 4-position and the other L¹ in a further position on thecinnoline ring may be the same or different) with a compound of theformula IV as hereinbefore defined, the reaction for example beingeffected by a process as described in (a) above.

(v) Compounds of formula IX as defined hereinbefore and salts thereofmay for example be made by the reaction of compounds of formula V asdefined hereinbefore with compounds of the formula XXII:L¹-C₁₋₅alkyl-L¹  (XXII)(wherein L¹ is as hereinbefore defined) to give compounds of formula IXor salts thereof. The reaction may be effected for example by a processas described in (b) above.

(vi) Intermediate compounds wherein X¹ is —SO— or —SO₂— may be preparedby oxidation from the corresponding compound in which X¹ is —S— or —SO—(when X¹ is —SO₂— is required in the final product). Conventionaloxidation conditions and reagents for such reactions are well known tothe skilled chemist.

When a pharmaceutically acceptable salt of a compound of the formula Iis required, it may be obtained, for example, by reaction of saidcompound with, for example, an acid using a conventional procedure, theacid having a pharmaceutically acceptable anion.

Many of the intermediates defined herein, for example, those of theformulae IV, V, VII, IX and XX are novel and these are provided as afurther feature of the invention. The preparation of these compounds isas described herein and/or is by methods well known to persons skilledin the art of organic chemistry.

The identification of compounds which potently inhibit the tyrosinekinase activity associated with VEGF receptors such as Flt and/or KDRand which inhibit angiogenesis and/or increased vascular permeability isdesirable and is the subject of the present invention. These propertiesmay be assessed, for example, using one or more of the procedures setout below:

(a) In Vitro Receptor Tyrosine Kinase Inhibition Test

This assay determines the ability of a test compound to inhibit tyrosinekinase activity. DNA encoding VEGF, FGF or EGF receptor cytoplasmicdomains may be obtained by total gene synthesis (Edwards M,International Biotechnology Lab 5(3), 19-25, 1987) or by cloning. Thesemay then be expressed in a suitable expression system to obtainpolypeptide with tyrosine kinase activity. For example VEGF, FGF and EGFreceptor cytoplasmic domains, which were obtained by expression ofrecombinant protein in insect cells, were found to display intrinsictyrosine kinase activity. In the case of the VEGF receptor Flt (Genbankaccession number X51602), a 1.7 kb DNA fragment encoding most of thecytoplasmic domain, commencing with methionine 783 and including thetermination codon, described by Shibuya et al (Oncogene, 1990, 5:519-524), was isolated from cDNA and cloned into a baculovirustransplacement vector (for example pAcYM1 (see The BaculovirusExpression System: A Laboratory Guide, L. A. King and R. D. Possee,Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available fromInvitrogen Corporation)). This recombinant construct was co-transfectedinto insect cells (for example Spodoptera frugiperda 21 (Sf21)) withviral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus.(Details of the methods for the assembly of recombinant DNA moleculesand the preparation and use of recombinant baculovirus can be found instandard texts for example Sambrook et al, 1989, Molecular cloning—ALaboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press andO'Reilly et al, 1992, Baculovirus Expression Vectors—A LaboratoryManual, W. H. Freeman and Co, New York). For other tyrosine kinases foruse in assays, cytoplasmic fragments starting from methionine 806 (KDR,Genbank accession number L04947), methionine 668 (EGF receptor, Genbankaccession number X00588) and methionine 399 (FGF R1 receptor, Genbankaccession number X51803) may be cloned and expressed in a similarmanner.

For expression of cFlt tyrosine kinase activity, Sf21 cells wereinfected with plaque-pure cFlt recombinant virus at a multiplicity ofinfection of 3 and harvested 48 hours later. Harvested cells were washedwith ice cold phosphate buffered saline solution (PBS) (10 mM sodiumphosphate pH7.4, 138 mM sodium chloride, 2.7 mM potassium chloride) thenresuspended in ice cold HNTG/PMSF (20 mM Hepes pH7.5, 150 mM sodiumchloride, 10% V/V glycerol, 1% v/v Triton X100, 1.5 mM magnesiumchloride, 1M ethylene glycol-bis(βaminoethyl ether)N,N,N′,N′-tetraacetic acid (EGTA), 1 mM PMSF (phenylmethylsulphonylfluoride); the PMSF is added just before use from a freshly-prepared 100mM solution in methanol) using 1 ml HNTG/PMSF per 10 million cells. Thesuspension was centrifuged for 10 minutes at 13,000 rpm at 4° C., thesupernatant (enzyme stock) was removed and stored in aliquots at −70° C.Each new batch of stock enzyme was titrated in the assay by dilutionwith enzyme diluent (100 MM Hepes pH 7.4, 0.2 mM sodium orthovanadate,0.1% v/v Triton X100, 0.2 mM dithiothreitol). For a typical batch, stockenzyme is diluted 1 in 2000 with enzyme diluent and 50 μl of diluteenzyme is used for each assay well.

A stock of substrate solution was prepared from a random copolymercontaining tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (SigmaP3899), stored as 1 mg/ml stock in PBS at −20° C. and diluted 1 in 500with PBS for plate coating.

On the day before the assay 100 μl of diluted substrate solution wasdispensed into all wells of assay plates (Nunc maxisorp 96-wellimmunoplates) which were sealed and left overnight at 4° C.

On the day of the assay the substrate solution was discarded and theassay plate wells were washed once with PBST (PBS containing 0.05% v/vTween 20) and once with 50 mM Hepes pH7.4.

Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25 μlof diluted compound was transferred to wells in the washed assay plates.“Total” control wells contained 10% DMSO instead of compound. Twentyfive microlitres of 40 mM manganese(II)chloride containing 8 μMadenosine-5′-triphosphate (ATP) was added to all test wells except“blank” control wells which contained manganese(II)chloride without ATP.To start the reactions 50 μl of freshly diluted enzyme was added to eachwell and the plates were incubated at room temperature for 20 minutes.The liquid was then discarded and the wells were washed twice with PBST.One hundred microlitres of mouse IgG anti-phosphotyrosine antibody(Upstate Biotechnology Inc. product 05-321), diluted 1 in 6000 with PBSTcontaining 0.5% w/v bovine serum albumin (BSA), was added to each welland the plates were incubated for 1 hour at room temperature beforediscarding the liquid and washing the wells twice with PBST. One hundredmicrolitres of horse radish peroxidase (HRP)-linked sheep anti-mouse Igantibody (Amersham product NXA 931), diluted 1 in 500 with PBSTcontaining 0.5% w/v BSA, was added and the plates were incubated for 1hour at room temperature before discarding the liquid and washing thewells twice with PBST. One hundred microlitres of2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) solution,freshly prepared using one 50 mg ABTS tablet (Boehringer 1204 521) in 50ml freshly prepared 50 mM phosphate-citrate buffer pH5.0+0.03% sodiumperborate (made with 1 phosphate citrate buffer with sodium perborate(PCSB) capsule (Sigma P4922) per 100 ml distilled water), was added toeach well. Plates were then incubated for 20-60 minutes at roomtemperature until the optical density value of the “total” controlwells, measured at 405 nm using a plate reading spectrophotometer, wasapproximately 1.0. “Blank” (no ATP) and “total” (no compound) controlvalues were used to determine the dilution range of test compound whichgave 50% inhibition of enzyme activity.

(b) In Vitro HUVEC Proliferation Assay

This assay determines the ability of a test compound to inhibit thegrowth factor-stimulated proliferation of human umbilical veinendothelial cells (HUVEC).

HUVEC cells were isolated in MCDB 131 (Gibco BRL) +7.5% v/v foetal calfserum (FCS) and were plated out (at passage 2 to 8), in MCDB 131+2% v/vFCS+3 μg/ml heparin+1 μg/ml hydrocortisone, at a concentration of 1000cells/well in 96 well plates. After a minimum of 4 hours they were dosedwith the appropriate growth factor (i.e. VEGF 3 ng/ml, EGF 3 ng/ml orb-FGF 0.3 ng/ml) and compound. The cultures were then incubated for 4days at 37° C. with 7.5% CO₂. On day 4 the cultures were pulsed with 1μCi/well of tritiated-thymidine (Amersham product TRA 61) and incubatedfor 4 hours. The cells were harvested using a 96-well plate harvester(Tomtek) and then assayed for incorporation of tritium with a Beta platecounter. Incorporation of radioactivity into cells, expressed as cpm,was used to measure inhibition of growth factor-stimulated cellproliferation by compounds.

(c) In Vivo Solid Tumour Disease Model

This test measures the capacity of compounds to inhibit solid tumourgrowth.

CaLu-6 tumour xenografts were established in the flank of female athymicSwiss nu/nu mice, by subcutaneous injection of 1×10⁶ CaLu-6 cells/mousein 100 μl of a 50% (v/v) solution of Matrigel in serum free culturemedium. Ten days after cellular implant, mice were allocated to groupsof 8-10, so as to achieve comparable group mean volumes. Tumours weremeasured using vernier calipers and volumes were calculated as:(l×w)×√(l×w)×(π/6), where l is the longest diameter and w the diameterperpendicular to the longest. Test compounds were administered orallyonce daily for a minimum of 21 days, and control animals receivedcompound diluent. Tumours were measured twice weekly. The level ofgrowth inhibition was calculated by comparison of the mean tumour volumeof the control group versus the treatment group using a Student T testand/or a Mann-Whitney Rank Sum Test. The inhibitory effect of compoundtreatment was considered significant when p<0.05.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula Ias defined hereinbefore or a pharmaceutically acceptable salt thereof,in association with a pharmaceutically acceptable excipient or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) forexample as a sterile solution, suspension or emulsion, for topicaladministration for example as an ointment or cream or for rectaladministration for example as a suppository. In general the abovecompositions may be prepared in a conventional manner using conventionalexcipients.

The compositions of the present invention are advantageously presentedin unit dosage form. The compound will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremeter body area of the animal, i.e. approximately 0.1-100 mg/kg. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged and this normally provides a therapeutically-effective dose. Aunit dose form such as a tablet or capsule will usually contain, forexample 1-250 mg of active ingredient.

According to a further aspect of the present invention there is provideda compound of the formula I or a pharmaceutically acceptable saltthereof as defined hereinbefore for use in a method of treatment of thehuman or animal body by therapy.

We have found that compounds of the present invention inhibit VEGFreceptor tyrosine kinase activity and are therefore of interest fortheir antiangiogenic effects and/or their ability to cause a reductionin vascular permeability.

A further feature of the present invention is a compound of formula I,or a pharmaceutically acceptable salt thereof, for use as a medicament,conveniently a compound of formula I, or a pharmaceutically acceptablesalt thereof, for use as a medicament for producing an antiangiogenicand/or vascular permeability reducing effect in a warm-blooded animalsuch as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of the formula I, or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for use in theproduction of an antiangiogenic and/or vascular permeability reducingeffect in a warm-blooded animal such as a human being.

According to a further feature of the invention there is provided amethod for producing an antiangiogenic and/or vascular permeabilityreducing effect in a warm-blooded animal, such as a human being, in needof such treatment which comprises administering to said animal aneffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof as defined hereinbefore.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1-50 mg/kg is employed. However the daily dose willnecessarily be varied depending upon the host treated, the particularroute of administration, and the severity of the illness being treated.Accordingly the optimum dosage may be determined by the practitioner whois treating any particular patient.

The antiangiogenic and/or vascular permeability reducing treatmentdefined hereinbefore may be applied as a sole therapy or may involve, inaddition to a compound of the invention, one or more other substancesand/or treatments. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of the individualcomponents of the treatment. In the field of medical oncology it isnormal practice to use a combination of different forms of treatment totreat each patient with cancer. In medical oncology the othercomponent(s) of such conjoint treatment in addition to theantiangiogenic and/or vascular permeability reducing treatment definedhereinbefore may be: surgery, radiotherapy or chemotherapy. Suchchemotherapy may cover three main categories of therapeutic agent:

-   (i) other antiangiogenic agents that work by different mechanisms    from those defined hereinbefore (for example linomide, inhibitors of    integrin αvβ3 function, angiostatin, razoxin, thalidomide), and    including vascular targeting agents (for example combretastatin    phosphate and the vascular damaging agents described in    International Patent Application Publication No. WO 99/02166 the    entire disclosure of which document is incorporated herein by    reference, (for example N-acetylcolchinol-O-phosphate), and in    International Patent Application Publication No. WO 00/40529 the    entire disclosure of which document is incorporated herein by    reference);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene),    progestogens (for example megestrol acetate), aromatase inhibitors    (for example anastrozole, letrazole, vorazole, exemestane),    antiprogestogens, antiandrogens (for example flutamide, nilutamide,    bicalutamide, cyproterone acetate), LHRH agonists and antagonists    (for example goserelin acetate, luprolide), inhibitors of    testosterone 5α-dihydroreductase (for example finasteride),    anti-invasion agents (for example metalloproteinase inhibitors like    marimastat and inhibitors of urokinase plasminogen activator    receptor function) and inhibitors of growth factor function, (such    growth factors include for example platelet derived growth factor    and hepatocyte growth factor such inhibitors include growth factor    antibodies, growth factor receptor antibodies, tyrosine kinase    inhibitors and serine/threonine kinase inhibitors); and-   (iii) antiproliferative/antineoplastic drugs and combinations    thereof, as used in medical oncology, such as antimetabolites (for    example antifolates like methotrexate, fluoropyrimidines like    5-fluorouracil, purine and adenosine analogues, cytosine    arabinoside); antitumour antibiotics (for example anthracyclines    like doxorubicin, daunomycin, epirubicin and idarubicin,    mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for    example cisplatin, carboplatin); alkylating agents (for example    nitrogen mustard, melphalan, chlorambucil, busulphan,    cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic    agents (for example vinca alkaloids like vincristine and taxoids    like taxol, taxotere); topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan, and also irinotecan); also enzymes (for example    asparaginase); and thymidylate synthase inhibitors (for example    raltitrexed);    and additional types of chemotherapeutic agent include:-   (iv) biological response modifiers (for example interferon); and-   (v) antibodies (for example edrecolomab).

For example such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of a compound offormula I as defined hereinbefore, and a vascular targeting agentdescribed in WO 99/02166 such as N-acetylcolchinol-O-phosphate (Example1 of WO 99/02166).

As stated above the compounds defined in the present invention are ofinterest for their antiangiogenic and/or vascular permeability reducingeffects. Such compounds of the invention are expected to be useful in awide range of disease states including cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation, excessive scar formation and adhesions, lynmphoedema,endometriosis, dysfunctional uterine bleeding and ocular diseases withretinal vessel proliferation. In particular such compounds of theinvention are expected to slow advantageously the growth of primary andrecurrent solid tumours of, for example, the colon, breast, prostate,lungs and skin. More particularly such compounds of the invention areexpected to inhibit the growth of those primary and recurrent solidtumours which are associated with VEGF, especially those tumours whichare significantly dependent on VEGF for their growth and spread,including for example, certain tumours of the colon, breast, prostate,lung, vulva and skin.

In addition to their use in therapeutic medicine, the compounds offormula I and their pharmaceutically acceptable salts are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof VEGF receptor tyrosine kinase activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents.

It is to be understood that where the term “ether” is used anywhere inthis specification it refers to diethyl ether.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at ambient temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus, an oil-bath apparatus or aKoffler hot plate apparatus.

(vi) the structures of the end-products of the formula I were confirmedby nuclear (generally proton) magnetic resonance (NMR) and mass spectraltechniques; proton magnetic resonance chemical shift values weremeasured on the delta scale and peak multiplicities are shown asfollows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q,quartet, quin, quintet;

(vii) intermediates were not generally fully characterised and puritywas assessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;

(viii) HPLC were run under 2 different conditions:

-   1) on a TSK Gel super ODS 2 μM 4.6 mm×5 cm column, eluting with a    gradient of methanol in water (containing 1% acetic acid) 20 to 100%    in 5 minutes. Flow rate 1.4 ml/minute. Detection: U.V. at 254 nm and    light scattering detections;-   2) on a TSK Gel super ODS 2 μM 4.6 mm×5 cm column, eluting with a    gradient of methanol in water (containing 1% acetic acid) 0 to 100%    in 7 minutes. Flow rate 1.4 ml/minute. Detection: U.V. at 254 nm and    light scattering detections.

(ix) petroleum ether refers to that fraction boiling between 40-60° C.

(x) the following abbreviations have been used:

-   -   DMF N,N-dimethylformamide    -   DMSO dimethylsulphoxide    -   TFA trifluoroacetic acid    -   NMP 1-methyl-2-pyrrolidinone    -   THF tetrahydrofuran    -   HMDS 1,1,1,3,3,3-hexamethyldisilazane.    -   HPLC RT HPLC retention time    -   DEAD diethyl azodicarboxylate    -   DMA dimethylacetamide    -   DMAP 4-dimethylaminopyridine

EXAMPLE 1

A suspension of4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (60 mg, 0.187mmol), 4-fluoro-5-hydroxy-2-methylindole (46 mg, 0.28 mmol) and cesiumcarbonate (121 mg, 0.37 mmol) in DMA (2 ml) was heated at 100° C. for 2hours. The volatiles were removed under vacuum and the residue waspurified by column chromatography eluting with methanol/methylenechloride (5/95) followed by methanol saturated with ammonia/methylenechloride (5/95). The fractions containing the expected product werecombined and evaporated. The residue was triturated with a mixture ofpentane/ether. The solid was filtered, washed with pentane and driedunder vacuum to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline(32 mg, 38%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.85-2.0 (m, 2H); 2.0-2.2 (m, 2H);2.25-2.4 (m, 2H); 2.45 (s,3H); 3.02-3.18 (m, 2H); 3.32-3.45 (m, 2H);3.68 (m, 2H); 4.16 (s, 3H); 4.46 (t, 2H); 6.35 (s, 0.5 H; partlyexchanged); 7.15 (dd, 1H); 7.3 (d, 1H); 7.78 (s, 1H); 7.84 (s, 1H); 8.73(s, 1H).

MS-ESI: 451 [MH]⁺.

The starting material was prepared as follows:

To a suspension of sodium hydride (5.42 g, 226 mmol) (prewashed withpentane) in THF (100 ml) cooled at 10° C. was added ethyl acetoacetate(29.4 g, 226 mmol) while keeping the temperature below 15° C. Aftercompletion of addition, the mixture was further stirred for 15 minutesand cooled to 5° C. A solution of 1,2,3-trifluoro-4-nitrobenzene (20 g,113 mmol) in THF (150 ml) was added while keeping the temperature below5° C. The mixture was then left to warm up to ambient temperature andstirred for 24 hours. The volatiles were removed under vacuum and theresidue was partitioned between ethyl acetate and 2N aqueoushydrochloric acid. The organic layer was washed with water, brine, dried(MgSO₄) and evaporated. The residue was dissolved in concentratedhydrochloric acid (650 ml) and acetic acid (600 ml) and the mixture wasrefluxed for 15 hours. After cooling, the volatiles were removed undervacuum and the residue was partitioned between aqueous sodium hydrogencarbonate (5%) and ethyl acetate. The organic layer was washed withsodium hydrogen carbonate, water, brine, dried (MgSO₄) and evaporated.The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (75/25) to give3-acetylmethyl-1,2-difluoro-4-nitrobenzene (17.5 g, 72%).

¹H NMR Spectrum: (CDCl₃) 2.4 (s, 3H); 4.25 (s, 2H); 7.25 (dd, 1H); 8.0(dd, 1H).

A solution of 3-acetylmethyl-1,2-difluoro-4-nitrobenzene (500 mg, 2.3mmol) in methylene chloride (5 ml) containing montmorillonite K10 (1 g)and trimethyl orthoformate (5 ml) was stirred for 24 hours at ambienttemperature. The solid was filtered, washed with methylene chloride andthe filtrate was evaporated to give1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (534 mg, 88%).

¹H NMR Spectrum: (CDCl₃) 1.2 (s, 3H); 3.2 (s, 6H); 3.52 (s, 2H); 7.18(dd, 1H); 7.6 (m, 1H).

To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) wasadded 60% sodium hydride (82 mg, 2.05 mmol). The mixture was stirred for1 hour at ambient temperature. A solution of1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (534 mg, 2.05 mmol)in DMA (1.5 ml) was added and the mixture was stirred for 3 hours atambient temperature. The mixture was diluted with 1N hydrochloric acid(10 ml) and extracted with ethyl acetate. The organic layer wasevaporated and the residue was dissolved in TBF (2 ml) and 6Nhydrochloric acid (0.3 ml) was added. The mixture was stirred for 1 hourat ambient temperature and the solvents were removed under vacuum. Theresidue was partitioned between ethyl acetate and water. The organiclayer was separated, washed with brine, dried (MgSO₄) and evaporated.The solid was triturated with ether, filtered, washed with ether anddried under vacuum to give3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (350 mg, 56%).

¹H NMR Spectrum: (CDCl₃) 2.35 (s, 3H); 4.25 (s, 2H); 5.25 (s, 2H); 7.0(dd, 1H); 7.32-7.5 (m, 5H); 8.0 (dd, 1H).

A solution of 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (300mg, 0.99 mmol) in ethanol (10 ml) and acetic acid (1 ml) containing 10%palladium on charcoal (30 mg) was hydrogenated at 2 atmospheres pressurefor 2 hours. The mixture was filtered and the filtrate was evaporated.The residue was dissolved in ethyl acetate and the organic layer waswashed with aqueous sodium hydrogen carbonate, brine and evaporated togive 4-fluoro-5-hydroxy-2-methylindole. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (317)to give 4-fluoro-5-hydroxy-2-methylindole (63 mg, 30%).

MS-ESI: 166 [MH]⁺.

¹H NMR Spectrum: (DMSOd₆) 2.35 (s, 3H); 6.05 (s, 1H); 6.65 (dd, 1H); 6.9(d, 1H); 8.75 (s, 1H); 10.9 (s, 1H).

¹³C NMR Spectrum: (DMSOd₆) 13.5 ; 94,0; 106,0; 112; 118.5 (d); 132 (d);136 (d); 136.5; 142.5 (d).

Alternatively the 4-fluoro-5-hydroxy-2-methylindole may be prepared asfollows:

To a solution of 2-fluoro-4-nitroanisole (9.9 g, 58 mmol) and4-chlorophenoxyacetonitrile (10.7 g, 64 mmol) in DMF (50 ml) cooled at−15° C. was added potassium tert-butoxide (14.3 g, 127 mmol) in DMF (124ml). After stirring for 30 minutes at −15° C., the mixture was pouredonto cooled 1N hydrochloric acid. The mixture was extracted with ethylacetate. The organic layer was washed with 1N sodium hydroxide, brine,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with methylene chloride. The fractions containingthe expected product were combined and evaporated. The residue wasdissolved in ethanol (180 ml) and acetic acid (24 ml) containing 10%palladium on charcoal (600 mg) and the mixture was hydrogenated under 3atmospheres pressure for 2 hours. The mixture was filtered, and thevolatiles were removed under vacuum. The residue was partitioned betweenethyl acetate and water. The organic layer was separated, and washedwith saturated sodium hydrogen carbonate followed by brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with methylene chloride to give a mixture of4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole (5.64 g, 59%) in aratio 1/2.

¹H NMR Spectrum: (DMSOd₆) 3.85 (s, 3H); 6.38 (s, 1H, 6-Fluoro); 6.45 (s,1H; 4-Fluoro); 6.9-7.4 (m, 3H)

A solution of 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole in aratio 1/2 (496 mg, 3 mmol), di-tertbutyl dicarbonate (720 mg, 3.3 mmol)in acetonitrile (12 ml) containing DMAP (18 mg, 0.15 mmol) was stirredat ambient temperature for 24 hours. The volatiles were removed undervacuum. The residue was dissolved in ethyl acetate, washed with 1Nhydrochloric acid, followed by water, brine, dried (MgSO₄) andevaporated to give a mixture of4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and6-fluoro-5-methoxy-1-tert-butoxycarbonylindole in a ratio 1/2(702 mg,88%).

¹H NMR Spectrum: (DMSOd₆) 1.65 (s, 9H); 3.9 (s, 3H); 6.6 (d, 1H,6-fluoro); 6.72 (d, 1H, 4-fluoro); 7.2 (t, 1H, 6-fluoro); 7.4 (d, 1H,4-fluoro); 7.62 (d, 1H, 6-fluoro); 7.68 (d, 1H, 4-fluoro); 7.78 (s, 1H,4-fluoro); 7.85 (s, 1H, 6-fluoro)

To a solution of 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and6-fluoro-5-methoxy-1-tert-butoxycarbonylindole in a ratio 1/2 (8.1 g,30.5 mmol) in TMF (100 ml) cooled at −65° C. was added tert-butyllithium(1.7 M) (23 ml, 35.7 mmol). After stirring for 4 hours at −70° C.,methyl iodide (8.66 g, 61 mmol) was added and the mixture was left towarm-up to ambient temperature. Water was added and the mixture wasextracted with ether. The organic layer was washed with water, brine,dried (MgSO₄) and evaporated and was used directly in the next step.

The crude product was dissolved in methylene chloride (100 ml) and TFA(25 ml) was added. After stirring for 1 hour at ambient temperature, thevolatiles were removed under vacuum. The residue was dissolved in ethylacetate and the organic layer was washed with 1N sodium hydroxide,followed by water, brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography, eluting with ethyl acetate/petroleumether (3/7) to give 6-fluoro-5-methoxy-2-methylindole (1.6 g) and4-fluoro-5-methoxy-2-methylindole (0.8 g, 48%)

6-fluoro-5-methoxy-2-methylindole:

MS-ESI: 180 [MH]⁺.

¹H NMR Spectrum: (DMSOd₆) 2.35 (s, 3H); 3.8 (s, 3H); 6.05 (s, 1H); 7.1(s, 1H); 7.12 (s, 1H); 10.8 (s, 1H).

4-fluoro-5-methoxy-2-methylindole:

MS-ESI: 180 [MH]⁺.

¹H NMR Spectrum: (DMSOd₆) 2.35 (s, 3H); 3.8 (s, 3H); 6.15 (s, 1H); 6.9(t, 1H); 7.05 (d, 1H); 11.0 (s, 1H).

To a solution of 4-fluoro-5-methoxy-2-methylindole (709 mg, 3.95 mmol)in methylene chloride (9 ml) cooled at −30° C. was added a solution ofboron tribromide (2.18 g, 8.7 mmol) in methylene chloride (1 ml). Afterstirring for 1 hour at ambient temperature, the mixture was poured ontowater and was diluted with methylene chloride. The pH of the aqueouslayer was adjusted to 6. The organic layer was separated, washed withwater, brine, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography, eluting with ethyl acetate/petroleum ether (3/7)to give 4-fluoro-5-hydroxy-2-methylindole (461 mg, 70%).

MS-ESI: 166 [MH]⁺.

¹H NMR Spectrum: (DMSOd₆) 2.35 (s, 3H); 6.05 (s, 1H); 6.65 (dd, 1H); 6.9(d, 1H); 8.75 (s, 1H); 10.9 (s, 1H).

¹³C NMR Spectrum: (DMSOd₆) 13.5 ; 94.0; 106.0; 112; 118.5 (d); 132 (d);136 (d); 136.5; 142.5 (d).

Alternatively the 4-fluoro-5-hydroxy-2-methylindole may be prepared asfollows:

A solution of sodium methoxide (freshly prepared from sodium (1.71 g)and methanol (35 ml)) was added to a solution of1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (16.2 g, 62 mmol),(prepared as described above), in methanol (200 ml) cooled at 5° C. Themixture was left to warm to ambient temperature and was stirred for 3days. The volatiles were removed under vacuum and the residue waspartitioned between ethyl acetate and 2N hydrochloric acid (1 ml). Theorganic layer was concentrated to a total volume of 100 ml and THF (100ml) and 6N hydrochloric acid (25 ml) were added. The mixture was stirredfor 1 hour at ambient temperature. The volatiles were removed undervacuum and the residue was partitioned between ethyl acetate and water.The organic layer was separated, washed with water, brine, dried (MgSO₄)and evaporated. The residue was purified by column chromatographyeluting with ethyl acetate/petroleum ether (3/7) to give3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (12.7 g, 90%).

MS-ESI: 250 [MNa]+.

¹H NMR Spectrum: (CDCl₃) 2.38 (s, 3H); 4.0 (s, 3H); 4.25 (s, 2H); 7.0(dd, 1H); 8.05 (d, 1H).

To a solution of 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (11.36g, 50 mmol) in acetone (200 ml) was added 4M aqueous ammonium acetate(700 ml) followed by a solution of titanium trichloride (15% in water,340 ml) dropwise. The mixture was stirred for 10 minutes at ambienttemperature and the mixture was extracted with ether. The organic layerwas washed with 0.5N aqueous sodium hydroxide followed by water, brine,dried (MgSO₄) and the volatiles were removed under vacuum. The residuewas purified by column chromatography eluting with methylene chloride togive 4-fluoro-5-methoxy-2-methylindole (8.15 g, 90%).

¹H NMR Spectrum: (DMSO) 2.35 (s, 3H); 3.8 (s, 3H); 6.1 (s, 1H); 6.85(dd, 1H); 7.02 (d, 1H).

Cleavage of 4-fluoro-5-methoxy-2-methylindole with boron tribromide togive 4-fluoro-5-hydroxy-2-methylindole is described above.

Pyrrolidine (50 g, 700 mmol), 3-chloropropanol (58.5 ml, 700 mmol) andpotassium carbonate (145 g, 1.05 mol) were refluxed in acetonitrile (1l) for 20 hours. Upon cooling to ambient temperature the precipitate wasfiltered off and rinsed with acetonitrile. The solvent was evaporatedoff and the residual oil purified by distillation under vacuum to give3-(pyrrolidin-1-yl)propan-1-ol (62.1 g, 69%).

¹H NMR Spectrum: (CDCl₃) 1.75 (m, 6H); 2.55 (m, 4H); 2.75 (t, 2H); 3.85(t, 2H); 5.50 (br s, 1H).

To a solution of 4-chloro-7-hydroxy-6-methoxycinnoline (300 mg, 1.42mmol), triphenylphosphine (747 mg, 2.85 mmol) and3-(pyrrolidin-1-yl)propan-1-ol (276 mg, 2.1 mmol) in methylene chloride(12 ml) was added diethyl azodicarboxylate (449 μl, 2.85 mmol) dropwiseand the mixture was stirred for 2 hours at ambient temperature. Thevolatiles were removed under vacuum and the residue was purified bycolumn chromatography eluting with methylene chloride/methanol (90/10)followed by methylene chloride/methanol/methanol saturated with ammonia(89/10/1 followed by 85/10/5). The fractions containing the expectedproduct were combined and evaporated to give4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (80 mg, 18%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.8-2.0 (m, 2H); 2.0-2.15 (m, 2H);2.3 (t, 2H); 3.05-3.15 (m, 2H)); 3.4 (t, 2H); 3.7 (m, 2H); 4.15 (s, 3H);4.45 (t, 2H); 7.45 (s, 1H); 7.9 (s, 1H); 9.5 (s, 1H).

Mass spectrum: 322 [MH]⁺.

A solution of 7-benzyloxy-4-chloro-6-methoxycinnoline hydrochloride(3.06 g, 9 mmol), in TFA (30 ml) was heated at reflux for 5 hours. Afterevaporation of the solvent, the residue was suspended in water andadjusted to pH7 with saturated aqueous sodium hydrogen carbonatesolution. The resulting solid was filtered off, washed with water andether and dried under vacuum to give4-chloro-7-hydroxy-6-methoxycinnoline as a yellow solid (1.78 g, 94%).

A solution of 4-chloro-7-hydroxy-6-methoxycinnoline (400 mg) wasdissolved in methylene chloride (15 ml) and washed with saturated sodiumhydrogen carbonate. The organic layer was separated, washed with water,brine, dried (MgSO₄) and evaporated to give4-chloro-7-hydroxy-6-methoxycinnoline free base (300 mg).

The starting material, 7-benzyloxy-4-chloro-6-methoxycinnolinehydrochloride, was obtained by heating a solution of7-benzyloxy-4-hydroxy-6-methoxycinnoline (11 g, 39 mmol) in thionylchloride (180 ml) containing DMF (1 ml) at reflux for 1 hour. Aftercooling, excess thionyl chloride was removed by evaporation andazeotroped with toluene. The residue was triturated with ether, filteredoff, washed with ether and dried under vacuum to give7-benzyloxy-4-chloro-6-methoxycinnoline hydrochloride as a cream solid(13.6 g, quantitative).

The starting material 7-benzyloxy-4-hydroxy-6-methoxycinnoline wasobtained by dropwise addition of a solution of sodium nitrite (4.9 g,0.072 mol) in water (10 ml) to a solution of2-amino-4-benzyloxy-5-methoxyacetophenone (16.3 g 0.06 mol) in aceticacid (250 ml) and 70% sulphuric acid (7.3 ml). After stirring for 30minutes, triethylamine (25 ml) was added and stirring was continued for6 hours. After adjusting to pH3.2 with 2M aqueous sodium hydroxidesolution, the solid was filtered off, washed with water, ether and driedunder vacuum to give 7-benzyloxy-4-hydroxy-6-methoxycinnoline (12.76 g,75%) as a brown solid.

m.p. 262-264° C.

The starting material 2-amino-4-benzyloxy-5-methoxyacetophenone wasobtained by adding powdered iron (520 mg, 9.3 mmol) to a solution of2-nitro-4-benzyloxy-5-methoxyacetophenone (1 g, 3.3 mmol) in acetic acid(5 ml) heated at 100° C. After 30 minutes, the reaction mixture wascooled to ambient temperature and diluted with water. After extractionwith ethyl acetate the organic layer was washed with water, brine, dried(MgSO₄) and the solvent evaporated. The residue was purified by flashchromatography using petroleum ether/ethyl acetate (3/1) as eluent togive 2-amino-4-benzyloxy-5-methoxyacetophenone (629 mg, 70%) as a yellowsolid.

m.p. 139-141° C.

The starting material 2-nitro-4-benzyloxy-5-methoxyacetophenone wasobtained by, addition of a suspension of tin(IV)chloride (15.8 ml, 0.13mol) and 69.5% nitric acid (9.1 ml, 0.2 mol) in methylene chloride (10ml), dropwise over a period of 20 minutes, to a solution of4-benzyloxy-3-methoxyacetophenone (28.9 g, 0.11 mol) in methylenechloride (400 ml) cooled at −35° C.

After stirring for 20 minutes at −25° C., the mixture was warmed toambient temperature and poured onto ice/water (1 litre). Afterextraction with methylene chloride the organic layer was washed withbrine, dried (MgSO₄) and the solvent evaporated. The residue waspurified by flash chromatography using petroleum ether/ethyl acetate(7/3) as eluent to give 2-nitro-4-benzyloxy-5-methoxyacetophenone (27 g,76%) as a yellow solid.

m.p. 134-136° C.

The starting material, 4-benzyloxy-3-methoxyacetophenone, was obtainedby heating a solution of 4-hydroxy-3-methoxyacetophenone (20 g, 0.12mol), benzyl bromide (15.7 ml, 0.13 mol) and potassium carbonate (49.8g, 0.36 mol) in DMF (400 ml) at 40° C. overnight. After cooling, themixture was diluted with water, acidified to approximately pH3 andextracted with ethyl acetate. The organic layer was washed with brine,dried (MgSO₄) and the solvent evaporated. The residue was purified byflash chromatography using petroleum ether/ethyl acetate (8/2 followedby 65/35) as eluent to give 4-benzyloxy-3-methoxyacetophenone (30.3 g,99%).

m.p. 86-88° C.

EXAMPLE 2

Using an analogous procedure to that described in Example 1,4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)cinnoline (100 mg, 0.32mmol) was reacted with 4-fluoro-5-hydroxy-2-methylindole (64 mg, 0.38mmol), (prepared as described for the starting material in Example 1),to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)cinnoline(26 mg, 19%).

¹H NMR Spectrum: (DMSOd₆) 2.45 (s, 3H); 3.25 (s, 3H); 3.5 (m, 2H); 3.65(m, 2H); 3.9 (m, 2H); 4.04 (s, 3H); 4.4 (m, 2H); 6.3 (s, 1H); 7.07 (dd,1H); 7.24 (d, 1H); 7.55 (s, 1H); 7.79 (s, 1H); 8.3 (s, 1H).

MS-ESI: 442 [MH]⁺.

The starting compound4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)cinnoline was obtainedby adding triphenylphosphine (995 mg, 3.8 mmol), followed bydiethyleneglycol (271 μl, 2.2 mmol) and diethyl azodicarboxylate (598μl, 3.8 mmol), dropwise, to a suspension of4-chloro-7-hydroxy-6-methoxycinnoline (0.4 g, 1.9 mmol), (prepared asdescribed for the starting material in Example 1), in methylene chloride(12 ml) under nitrogen and cooled to 10° C. After stirring for 1 hour,the solvent was evaporated and the residue purified by flashchromatography using methylene chloride/ethyl acetate (5/5 followed by4/6) as eluent to give4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)cinnoline (366 mg, 91%).

EXAMPLE 3

A mixture of 7-benzyloxy-4-chloro-6-methoxy cinnoline (2 g, 6.66 mmol),(prepared as described for the starting material in Example 1),4-fluoro-5-hydroxy-2-methylindole (1.32 g, 7.99 mmol), (prepared asdescribed for the starting material in Example 1), and cesium carbonate(3.2 g, 9.98 mmol) in DMF (40 ml) was heated at 95° C. for 1.5 hours.4-Fluoro-5-hydroxy-2-methylindole (82 mg, 0.5 mmol) and cesium carbonate(3.2 g, 9.98 mmol) were added. The mixture was stirred for 1.5 hours at115° C. The mixture was cooled, the solid was filtered and the filtratewas evaporated under vacuum. The residue was purified by columnchromatography, eluting with methylene chloride/ethyl acetate (90/10followed by 80/20) followed by methylene chloride/ethyl acetate/methanol(80/18/2). The fractions containing the expected product were combinedand evaporated and the residue was triturated with ether/pentane (1/1).The solid was filtered, washed with pentane and dried under vacuum togive 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(1.1 g, 39%).

¹H NMR Spectrum: (DMSOd₆) 2.43 (s, 3H); 4.04 (s, 3H); 5.4 (s, 2H); 6.3(s, 1H); 7.08 (dd, 1H); 7.25 (d, 1H); 7.35-7.5 (m, 3H); 7.55 (d, 2H);7.57 (s, 1H); 7.9 (s, 1H); 8.33 (s, 1H).

MS-ESI: 430 [MH]⁺.

EXAMPLE 4

A solution of7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (500mg, 1.17 mmol), (prepared as described in Example 3), ammonium formate(740 mg, 11.7 mmol), 10% palladium on charcoal (100 mg) and water (700μl) in DMF (10 ml) was stirred for 2 hours at ambient temperature. Themixture was filtered on diatomaceous earth and the filtrate wasevaporated under vacuum. The residue was triturated with a mixture ofether and pentane (1/1). The solid was filtered, washed with pentane anddried under vacuum to give4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (300 mg,quant.).

¹H NMR Spectrum: (DMSOd₆) 2.45 (s, 3H); 4.09 (s, 3H); 6.32 (br s, 1H);7.07 (dd, 1H), 7.25 (d, 1H); 7.55 (s, 1H); 7.62 (s, 1H); 8.28 (s, 1H).

MS-ESI: 340 [MH]⁺.

EXAMPLE 5

Under nitrogen a suspension of4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (100 mg,0.295 mmol), (prepared as described in Example 4),3-(1,1-dioxothiomorpholino)-1-propanoltosylate (123 mg, 0.354 mmol) andpotassium carbonate (81 mg, 0.59 mmol) in DMF (6 ml) was stirred for 2.5hours at 100° C. The mixture was poured onto water and extracted withethyl acetate. The organic layer was separated, washed with water,brine, dried (MgSO₄) and evaporated. The residue was triturated with amixture of ether/pentane (1/1), filtered, washed with pentane and driedunder vacuum to give7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(63 mg, 42%).

¹H NMR Spectrum: (DMSOd₆) 2.0 (m, 2H); 2.4 (s, 3H); 2.7 (m, 2H); 2.95(br s, 4H); 3.15 (br s, 4H); 4.1 (s, 3H); 4.35(m, 2H); 6.4 (s, 1H);7.05(dd, 1H); 7.3(d, 1H); 7.55 (s, 1H); 7.75 (s, 1H); 7.97 (s, 1H); 8.35(s, 1H); 11.5 (br s, 1H).

MS-ESI: 515 [MH]⁺.

The starting material was prepared as follows:

A mixture of 3-amino-1-propanol (650 μl, 8.4 mmol) and vinyl sulphone (1g, 8.4 mmol) was heated at 110° C. for 45 minutes. The mixture wasallowed to cool and was purified by column chromatography eluting withmethylene chloride/methanol (95/5) to give3-(1,1-dioxothiomorpholino)propan-1-ol (800 mg, 90%).

¹H NMR Spectrum: (CDCl₃) 1.7-1.8(m, 2H); 2.73 (t, 2H); 3.06 (br s, 8H);3.25 (s, 1H); 3.78 (t,2H).

MS-ESI: 194 [MH]⁺.

3-(1,1-Dioxothiomorpholino)-1-propanol (12 g, 62 mmol) was dissolvedinto tert-butylmethyl ether (400 ml). This solution was cooled to 0° C.before the addition of DABCO (1,4-diazabicyclo[2.2.2]octane, 13.93 g,124 mmol) followed by portionwise addition of tosyl chloride (17.8 g, 93mmol). The reaction mixture was stirred for 1 hour at 0° C. and for 3hours at ambient temperature. The solvent was evaporated off and theresidue taken up in methylene chloride. The organic salts were removedby filtration and the filtrate was purified by flash chromatographyusing methanol/methylene chloride (5/95) as eluent. Evaporation of thesolvents and trituration with ether gave3-(1,1-dioxothiomorpholino)-1-propanoltosylate (9.44 g, 44%) as a whitesolid.

¹H NMR Spectrum: (DMSOd₆) 1.75 (m, 2H); 2.45 (m, 5H); 2.75 (m, 4H); 3.0(m, 4H); 4.10 (t, 2H); 7.50 (d, 2H); 7.85 (d, 2H).

EXAMPLE 6

A solution of7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(100 mg, 0.186 mmol) in methylene chloride (3 ml) containing TFA (1 ml)was stirred at ambient temperature for 2 hours. The volatiles wereremoved under vacuum. The residue was partitioned between water andmethylene chloride and the pH of the aqueous layer was adjusted to 13with 6N aqueous sodium hydroxide. The organic layer was separated,washed with water, brine, dried (MgSO₄) and evaporated. The residue wastriturated with ether/pentane (1/1). The solid was filtered, washed withpentane and dried under vacuum to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(piperidin-4-ylmethoxy)cinnoline(50 mg, 62%).

¹H NMR Spectrum: (DMSOd₆) 1.15-1.3 (m, 2H); 1.78 (d, 2H); 1.9-2.05 (m,1H); 2.45 (s, 3H); 2.5-2.65 (m, 2H); 3.0 (d, 2H); 4.05 (s, 3H); 4.1 (d,2H); 6.3 (s, 1H); 7.05 (dd, 1H); 7.25 (d, 1H); 7.55 (s, 1H); 7.75 (s,1H); 8.32 (s, 1H).

MS-ESI: 436 [MH]⁺.

The starting material was prepared as follows:

While maintaining the temperature in the range 0-5° C., a solution ofdi-tert-butyl dicarbonate (41.7 g, 0.19 mol) in ethyl acetate (75 ml)was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0.19 mol) in ethyl acetate (150 ml) cooled at 5° C. After stirringfor 48 hours at ambient temperature, the mixture was poured onto water(300 ml). The organic layer was separated, washed successively withwater (200 ml), 0.1N aqueous hydrochloric acid (200 ml), saturatedsodium hydrogen carbonate (200 ml) and brine (200 ml), dried (MgSO₄) andevaporated to give ethyl4-(1-(tert-butoxycarbonyl)piperidine)carboxylate (48 g, 98%).

¹H NMR Spectrum: (CDCl₃) 1.25 (t, 3H); 1.45 (s, 9H); 1.55-1.70 (m, 2H);1.8-2.0(d, 2H); 2.35-2.5 (m, 1H); 2.7-2.95(t, 2H); 3.9-4.1 (br s, 2H);4.15 (q, 2H).

A solution of 1M lithium aluminum hydride in THF (133 ml, 0.133 mol) wasadded in portions to a solution of ethyl4-(1-(tert-butoxycarbonyl)piperidine)carboxylate (48 g, 0.19 mol) in dryTHF (180 ml) cooled at 0° C. After stirring at 0° C. for 2 hours, water(30 ml) was added followed by 2N sodium hydroxide (10 ml). Theprecipitate was removed by filtration through diatomaceous earth andwashed with ethyl acetate. The filtrate was washed with water, brine,dried (MgSO₄) and evaporated to give1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (36.3 g, 89%).

MS (EI): 215 [M.]+.

¹H NMR Spectrum: (CDCl₃) 1.05-1.2(m, 2H); 1.35-1.55(m, 10H); 1.6-1.8(m,2H); 2.6-2.8(t, 2H); 3.4-3.6(t, 2H); 4.0-4.2(br s, 2H).

1,4-Diazabicyclo[2.2.2]octane (42.4 g, 0.378 mol) was added to asolution of 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (52.5 g,0.244 mol) in tert-butyl methyl ether (525 ml). After stirring for 15minutes at ambient temperature, the mixture was cooled to 5° C. and asolution of toluene sulphonyl chloride (62.8 g, 0.33mmol) in tert-butylmethyl ether (525 ml) was added in portions over 2 hours whilemaintaining the temperature at 0° C. After stirring for 1 hour atambient temperature, petroleum ether (1l) was added. The precipitate wasremoved by filtration. The filtrate was evaporated to give a solid. Thesolid was dissolved in ether and washed successively with 0.5N aqueoushydrochloric acid (2×500 ml), water, saturated sodium hydrogen carbonateand brine, dried (MgSO₄) and evaporated to give1-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine(76.7 g, 85%).

MS (ESI): 392 [MNa]⁺.

¹H NMR Spectrum: (CDCl₃) 1.0-1.2(m, 2H); 1.45(s, 9H); 1.65(d, 2H);1.75-1.9(m, 2H); 2.45(s, 3H); 2.55-2.75(m, 2H); 3.85(d, 1H); 4.0-4.2(brs, 2H); 7.35(d, 2H); 7.8(d, 2H).

Under nitrogen a mixture of4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (150 mg,0.44 mmol), (prepared as described in Example 4),1-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine(196 mg, 0.53 mmol) and potassium carbonate (122 mg, 0.88 mmol) in DMF(6 ml) was stirred at 100° C. for 2.5 hours. The mixture was filtered,and filtrate was evaporated under vacuum. The residue was purified bycolumn chromatography eluting with methylene chloride followed bymethylene chloride/methanol (99/1 and 95/5). The fractions containingthe expected product were combined and evaporated. The residue wastriturated with a mixture of pentane/ether (1/1) and the solid wasfiltered, washed with pentane and dried under vacuum to give7-(1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(100 mg, 42%).

¹H NMR Spectrum: (DMSOd₆) 1.2-1.3 (m, 2H); 1.41 (s, 9H); 1.85 (d, 2H);2.1 (m, 1H); 2.42 (s, 3H); 2.8 (m, 2H); 4.0 (m, 2H); 4.05 (s, 3H); 4.15(d, 2H); 6.3 (s, 1H); 7.06 (dd, 1H); 7.25 (d, 1H); 7.55 (s, 1H); 7.75(s, 1H); 8.3 (s, 1H).

MS-ESI: 537 [MH]⁺.

EXAMPLE 7

Under nitrogen a solution of7-(R)-(2,3-epoxypropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6methoxycinnoline(110 mg, 0.278 mmol) and piperidine (83 μl, 0.835 mmol) in DMF (2 ml)was stirred at 60° C. for 3 hours. The volatiles were removed undervacuum and the residue was purified by column, chromatography elutingwith methylene chloride followed by methylene chloride/methanol (95/5)and methylene chloride/methanol saturated with ammonia (95/5 followed by90/10). The fractions containing the expected product were combined andevaporated. The residue was triturated with ether, filtered, washed withether and dried under vacuum to give4-(4-fluoro-2-methylindol-5-yloxy)-7-(R)-(2-hydroxy-3-(piperidin-1-yl)propoxy)-6-methoxycinnoline(65 mg, 49%).

¹H NMR Spectrum: (DMSOd6, CF₃COOD) 1.35-1.5 (m, 1H); 1.65-1.9 (m, 5H);2.45 (s, 3H); 2.9-3.1 (m, 2H); 3.2-3.4 (m, 2H); 3.5-3.6 (m, 2H); 4.15(s, 3H); 4.35 (br s, 2H); 4.52 (m, 1H); 6.3 (s, 0.3H, partly exchanged);7.1 (dd, 1H); 7.3 (d, 1H); 7.8 (s, 1H); 7.85 (s, 1H); 8.72 (s, 1H).

MS-ESI: 481 [MH]⁺.

The starting material was prepared as follows:

Under nitrogen a suspension of4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (150 mg,0.442 mmol), (prepared as described in Example 4),2-(R)-glycidyltosylate (121 mg, 0.53 mmol) and potassium carbonate (183mg, 1.32 mmol) in DMA (3 ml) was stirred at 60° C. for 3 hours. Themixture was then poured onto water and extracted with ethyl acetate. Theorganic layer was washed with aqueous ammonia, followed by water, brine,dried (MgSO₄) and evaporated. The residue was triturated with ether,filtered, washed with ether and dried under vacuum to give7-(R)-(2,3-epoxypropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(115 mg, 66%).

¹H NMR Spectrum: (DMSOd₆) 2.45 (s, 3H); 2.8 (dd, 1H); 2.92 (dd, 1H); 3.5(m, 1H); 4.05 (s, 3H); 4.1 (dd, 1H); 4.68 (dd, 1H); 6.3 (s, 1H), 7.1(dd, 1H); 7.25 (d, 1H); 7.58 (s, 1H); 7.8 (s, 1H); 8.35 (s, 1H).

MS-ESI: 396 [MH]⁺.

EXAMPLE 8

A mixture of7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)4chloro-6-methoxycinnoline(204 mg, 0.5 mmol), 5-hydroxy-2-methylindole (81 mg) and cesiumcarbonate (326 mg, 1 mmol) in DMF (2.5 ml) was stirred at 90° C. for 2hours. After cooling, the mixture was filtered, wash ed with DMF and thevolatiles were removed under vacuum. The crude product was dissolved inmethylene chloride (4 ml) containing TEA (1.5 ml) and was stirred atambient temperature for 1 hour. The volatiles were removed under vacuum.The residue was partitioned between methylene chloride and 1N aqueoussodium hydroxide. The organic layer was separated, dried (MgSO₄),filtered and evaporated. The residue was purified by columnchromatography eluting with a gradient of methylene chloride/methanolsaturated with ammonia (5/95 to 15/85). The fractions containing theexpected product were combined and evaporated. The residue wastriturated under diethyl ether and the precipitate was filtered, washedwith ether and dried under vacuum to give7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5yl)cinnoline(42 mg, 20%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.58-1.7 (m, 2H); 2.05 (d, 2H); 2.3(m, 1H); 2.45 (s, 3H); 3.02 (m, 2H); 4.18 (s, 3H); 4.3 (d, 2H); 6.22 (s,0.5H, partly exchanged); 7.05 (d, 1H); 7.5 (m, 2H); 7.75 (s, 1H); 7.82(s, 1H); 8.6 (s, 1H).

MS: 419.6 [MH]⁺.

The starting material was prepared as follows:

DEAD (1.46 g, 8.38 mmol) was added to a suspension of4-chloro-7-hydroxy-6-methoxycinnoline (1.47 g, 6.98 mmol), (prepared asdescribed for the starting material in Example 1),1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (1.65 g, 7.68 mmol),(prepared as described for the starting material in Example 6), andtriphenylphosphine (2.74 g) in methylene chloride (40 ml). The mixturewas stirred for 1 hour at ambient temperature, then poured onto silicaand eluted with a gradient of ethyl acetate in methylene chloride (30/70to 50/50). The fractions containing the expected product were combinedand evaporated to give7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-6-methoxycinnoline(561 mg, 58%).

MS (ESI): 408.5 and 410.5 [MH]⁺.

A solution of boron tribromide (32.5 ml, 341 mmol) in methylene chloride(60 ml) was added in portions to a solution of 5-methoxy-2-methylindole(25 g, 155 mmol) in methylene chloride (250 ml) cooled at −45° C. Afterstirring for 15 minutes at −30° C., the mixture was warmed up to ambienttemperature and stirred for 1 hour. Methylene chloride (300 ml) wasadded in portions and the mixture was cooled to 0° C. Water was added inportions and the mixture was adjusted to pH6 with 4N sodium hydroxide.The organic layer was separated. The aqueous layer was extracted withmethylene chloride and the organic layers were combined, washed withwater, brine, dried (MgSO₄) and the volatiles were removed byevaporation. The residue was purified by column chromatography elutingwith ethyl acetate/methylene chloride (1/9 followed by 15/85) to give5-hydroxy-2-methylindole (21.2 g, 93%).

EXAMPLE 9

Using an analogous procedure to that described in Example 8,7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-6-methoxycinnoline(204 mg, 0.5 mmol) was reacted with 6-hydroxy-2-methylindole (100 mg,0.55 mmol) to give7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-6-yloxy)cinnoline.The crude product was then treated with TFA to give6-methoxy-4-(2-methylindol-6-yloxy)-7-(piperidin-4-ylmethoxy)cinnoline(10 mg, 4%).

¹H NMR Spectrum: (DMSOd₆) 1.5-1.6 (m, 2H); 2.05 (d, 2H); 2.25 (m, 1H);2.45 (s, 3H); 2.5-2.6 (m, 2H); 2.98 (t, 2H); 4.05 (s, 3H); 4.25 (d, 2H);6.22 (s, 1H); 6.9 (dd, 1H); 7.22 (s, 1H); 7.55 (s, 1H); 7.8 (s, 1H); 8.4(s, 1H).

MS: 418.5 [MH]⁺.

EXAMPLE 10

To a solution of4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(piperidin-4-ylmethoxy)cinnoline(170 mg, 0.31 mmol), (prepared as described in Example 6), in methylenechloride (6 ml) and methanol (3 ml) was added a solution of sodiumacetate (25 mg, 0.31 mmol). Acetic acid (22 ml) and formaldehyde (37%)(50 ml) were added. The mixture was stirred for 5 minutes and triacetatesodium borohydride (100 mg, 0.46 mmol) was added in portions. Themixture was stirred at ambient temperature for 1 hour. The volatileswere removed under vacuum and the residue was dissolved in water and thepH was adjusted to 10 with 2N aqueous sodium hydroxide. The mixture wasextracted with ethyl acetate. The organic layer was washed with brine,dried (MgSO₄) and evaporated. The residue was triturated under diethylether, filtered, washed with ether and dried under vacuum to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)cinnoline(75 mg, 43%).

¹H NMR Spectrum: (DMSOd₆) 1.4-1.5 (m, 2H); 1.75 (d, 2H); 1.7-1.8 (m,1H); 1.9 (dd, 2H); 2.2 (s, 3H); 2.5 (s, 3H); 2.85 (d, 2H); 4.06 (s, 3H);4.14 (d, 2H); 6.33 (s, 1H); 7.1 (dd, 1H); 7.26 (d, 1H); 7.57 (s, 1H);7.76 (s, 1H); 8.34 (s, 1H); 11.5 (br s, 1H).

MS: 449.5 [MH]⁺.

EXAMPLE 11

A solution of7-(R)-(2,3-epoxypropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(400 mg, 1 mmol), (prepared as described for the starting material inExample 7), and pyrrolidine (0.42 ml) in DMF (10 ml) was stirred at 70°C. for 2 hours. After cooling the volatiles were removed under vacuumand the mixture was poured onto silica and eluted with methylenechloride/methanol (95/5 followed by 90/10) followed by methylenechloride/methanol saturated with ammonia (95/5 followed by 90/10). Thefractions containing the expected product were combined and evaporatedto give4-(4-fluoro-2-methylindol-5-yloxy)-7-(R)-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxycinnoline(200 mg, 43%).

¹H NMR Spectrum: (DMSOd₆) 1.87-2.1 (m, 4H); 2.4 (s, 3H); 3.1-3.2 (m,2H); 3.3-3.45 (m, 2H); 3.65 (m, 2H); 4.18 (s, 3H); 4.35 (br s, 2H);4.35-4.45 (m, 1H); 6.3 (s, 0.3H, partly exchanged); 7.1 (dd, 1H); 7.3(d, 1H); 7.8 (s, 1H); 8.82 (s, 1H); 8.7 (s, 1H).

MS: 467 [MH]⁺.

EXAMPLE 12

A suspension of4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (200 mg, 0.62mmol), (prepared as described for the starting material in Example 1),5-hydroxyindole (100 mg, 0.75 mmol) and potassium carbonate (129 mg,0.93 mmol) in DMF (3 ml) was stirred at 100° C. for 6 hours. Aftercooling, the volatiles were removed under vacuum and the residue waspurified by column chromatography eluting with methylenechloride/methanol saturated with ammonia (98/2 to 90/10). The fractionscontaining the expected product were combined and evaporated to give4-(indol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (40mg, 15%).

¹H NMR Spectrum: (DMSOd₆) 1.72 (br s, 4H); 2.05 (m, 2H); 2.5 (m, 4H);2.6 (dd, 2H); 4.05 (s, 3H); 4.32 (dd, 2H); 6.5 (br s, 1H); 7.05 (dd,1H); 7.45-7.6 (m, 4H); 7.75 (s, 1H); 8.38 (s, 1H).

MS: 419.5 [MH]⁺.

EXAMPLE 13

DEAD (0.19 ml, 1.2 mmol) was added dropwise to a solution of4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g,0.6 mmol), (prepared as described in Example 4),4-(2-hydroxyethoxy)pyridine (0.125 g, 0.9 mmol), (J. Chem. Soc. PerkinII, 1987, 1867), and triphenylphosphine (0.31 g, 1.2 mmol) in DMF (4ml). After stirring for 2 hours at ambient temperature, the volatileswere removed under vacuum to give an oil that crystallised on standing.The solid was triturated with methylene chloride, filtered, washed withmethylene chloride and dried under vacuum to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)cinnoline(90 mg, 33%).

¹H NMR Spectrum: (DMSO d₆) 2.45 (s, 3H); 4.08 (s, 3H); 4.6 (m, 2H); 4.7(m, 2H); 6.32 (s, 1H); 7.05-7.12 (m, 3H); 7.26 (d, 1H); 7.6 (s, 1H); 7.9(s, 1H); 8.36 (s, 1H); 8.45 (d, 2H).

MS: 461.5 [M+H]⁺.

EXAMPLE 14

A solution of 4-hydroxypiperidine (0.5 g, 4.95 mmol) and7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(0.3 g, 0.65 mmol) in DMF (4 ml) was stirred at 60° C. for 30 minutes.The volatiles were removed under vacuum and the residue was purified bycolumn chromatography eluting with ethyl acetate/methylene chloride(1/1) followed by ethyl acetate/methanol/methylene chloride (4/1/5)followed by methylene chloride/methanol saturated with ammonia (9/1).The fractions containing the expected product were combined andevaporated to give4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(4-hydroxypiperidin-1-yl)propoxy)-6-methoxycinnoline(25 mg, 8%).

MS: 481.6 [M+H]⁺.

The starting material was prepared as follows:

DEAD (0.47 ml, 2.95 mmol) was added dropwise to a solution of4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.5 g,1.47 mmol), (prepared as described in Example 4), 3-bromopropan-1-ol(0.2 ml, 2.21 mmol) and triphenylphosphine (0.78 g, 2.95 mmol) in DMF(10 ml). The mixture was stirred for 1 hour at ambient temperature andthe volatiles were removed under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/methylene chloride(1/1). The fractions containing the expected product were combined andevaporated to give7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(0.6 g, 88%) (purity 80%; contaminated by some triphenylphosphineoxide).

¹H NMR Spectrum: (DMSO d₆) 2.4 (m, 2H); 2.42 (s, 3H); 3.75 (dd, 2H);4.05 (s, 3H); 4.4 (m, 2H); 6.32 (s, 1H); 7.08 (dd, 1H); 7.28 (d, 1H);7.55 (m, 1H); 7.8 (s, 1H); 8.35 (s, 1H).

MS: 460-462 [M+H]⁺.

EXAMPLE 15

Diethyl azodicarboxylate (0.095 ml, 0.6 mmol) was added dropwise to asuspension of4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.1 g,0.3 mmol), prepared as described in Example 4),3-(4-cyanomethylpiperazin-1-yl)propan-1-ol (0.085 g, 0.45 mmol) andtriphenylphosphine (0.155 g, 0.6 mmol) in methylene chloride (2.5 ml).The mixture was stirred for 30 minutes at ambient temperature. Further3-(4-cyanomethylpiperazin-1-yl)propan-1-ol (0.085 g, 0.45 mmol),triphenylphosphine (0.155 g, 0.6 mmol) and diethyl azodicarboxylate(0.095 ml, 0.6 mmol) were added. The mixture was stirred for 30 minutesand the volatiles were removed under vacuum. The residue was purified bycolumn chromatography eluting with ethylacetate/methylene chloride (1/1)followed by methanol/ethyl acetate/methylene chloride (5/45/50 followedby 10/40/50 and 10/0/90). The fractions containing the expected productwere combined and evaporated to give7-(3-(4-cyanomethylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(0.035 g, 24%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.3-2.4 (m, 2H), 2.45 (s, 3H),2.55-2.7 (m, 2H), 3.0-3.2 (m, 4H), 3.4 (m, 2H), 3.6-3.75 (m, 2H), 3.95(s, 2H), 4.2 (s, 3H), 4.42 (m, 2H), 6.35 (s, 0.5H, partly exchanged),7.08 (dd, 1H), 7.3 (d, 1H), 7.8 (s, 1H); 7.9 (s, 1H), 8.75 (s, 1H).

MS: 505.6 (M+H)⁺.

The starting material was prepared as follows:

A solution of 1-piperazinecarboxaldehyde (25 g, 0.219 mol),3-bromo-1-propanol (33.5 g, 0.241 mol) and potassium carbonate (38 g,0.273 mol) in methanol (33 ml) was heated at reflux for 5 hours. Aftercooling, the solid was filtered, washed with methanol and the filtratewas evaporated. The residue was dissolved in methylene chloride andwashed with a small amount of water. The organic layer was washed withbrine, dried (MgSO₄), filtered and evaporated. The residue was purifiedby column chromatography eluting with methylene chloride/methanol (90/10followed by 80/20) to give4-(3-hydroxypropyl)-1-piperazinecarboxaldehyde (4.5 g, 12%).

¹H NMR Spectrum: (DMSOd₆) 1.55-1.7 (m, 2H), 2.2-2.4 (m, 6H), 3.3-3.5 (m,6H), 4.45 (br s, 1H), 8.0 (s, 1H).

A solution of 4-(3-hydroxypropyl)-1-piperazinecarboxaldehyde (4.45 g) inmethanol (10 ml) and 4N aqueous hydrogen chloride (15 ml) was stirred atambient temperature for 3 hours. The volatiles were removed under vacuumand the residue was partitioned between trichloromethane and aqueoussodium hydroxide (40%). The organic layer was separated, washed withbrine, dried (MgSO₄) and evaporated to give3-(piperazin-1-yl)propan-1-ol (2.35 g).

A solution of 3-(piperazin-1-yl)propan-1-ol (0.93 g, 6.45 mmol),chloroacetonitrile (0.58 g, 7.75 mmol), potassium carbonate (1.79 g,12.9 mmol) and sodium iodide (0.32 g, 1.93 mmol) in DMF (10 ml) wasstirred at ambient temperature overnight. The volatiles were removedunder vacuum and the residue was purified by column chromatographyeluting with ethylene chloride/methanol (95/5) to give3-(4-cyanomethylpiperazin-1-yl)propan-1-ol (0.84 g, 71%).

¹H NMR Spectrum: (DMSOd₆) 1.5-1.65 (m, 2H), 2.25-2.6 (m, 10H), 3.45 (t,2H), 3.7 (s, 2H), 4.45 (br s, 1H).

MS: 184 (M+H)⁺.

EXAMPLE 16

Under nitrogen, diethyl azodicarboxylate (0.19 ml, 1.2 mmol) was addeddropwise to a suspension of4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g,0.6 mmol), (prepared as described in Example 4), in DMF (4 ml)containing triphenylphosphine (0.31 g, 1.2 mmol) and3-(4-acetylpiperazin-1-yl)propan-1-ol (0.15 g, 0.9 mmol). After stirringfor 2 hours at ambient temperature, the volatiles were removed undervacuum. The residue was purified by column chromatography eluting withmethylene chloride, followed by ethyl acetate/methylene chloride (1/1)followed by methanol/ethyl acetate/methylene chloride (1/4/5) followedby methanol/methylene chloride (1/9). The fractions containing theexpected product were combined and evaporated to give7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline(0.11 g, 37%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.07 (s, 3H), 2.4 (m, 2H), 2.44 (s,3H), 2.85-3.25 (m, 3H), 3.3-3.5 (m, 3H); 3.6 (d, 2H)); 4.1 (d, 2H); 4.17(s, 3H); 4.45-4.55 (m, 3H); 6.34 (s, 0.5H, partly exchanged), 7.2 (dd,1H), 7.35 (d, 1H), 7.79 (s, 1H), 7.84 (s, 1H), 8.75 (s, 1H).

MS: 508 (M+H)⁺.

The starting material was prepared as follows:

A suspension of 1-acetylpiperazine (3.85 g, 0.03 mol) and3-bromopropan-1-ol (4 ml) containing potassium carbonate (8.3 g, 60mmol) in acetonitrile (30 ml) was stirred at 80° C. for 5 hours. Thesolid was filtered and the filtrate was evaporated. The residue waspurified by column chromatography eluting with ethanol/methylenechloride (1/9 followed by 3/7) to give3-(4-acetylpiperazin-1-yl)propan-1-ol (3.15 g, 56%).

¹H NMR Spectrum: (CDCl₃) 1.75 (m, 2H), 2.05 (s, 3H), 2.4-2.5 (m, 4H),2.6 (t, 2H), 3.45 (t, 2H), 3.6 (m, 2H), 3.8 (t, 2H), 4.6 (br s, 1H).

MS: 187.4 (M+H)⁺.

EXAMPLE 17

Using an analogous procedure to that described in Example 16,4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g,0.6 mmol), (prepared as described in Example 4), was reacted with1-(3-hydroxypropyl)-4-methylpiperazine (0.14 g, 0.9 mmol) to give4-(4-fluoro-2-methylindol-5-yl)oxy-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)cinnoline(80 mg, 28%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD 75° C.) 2.35 (m, 2H), 2.45 (s, 3H),2.98 (s, 3H), 3.43 (m, 2H), 3.6 (m, 8H), 4.19 (s, 3H), 4.5 (m, 2H), 6.35(br s, 0.3H partly exchanged), 7.15 (m, 1H), 7.3 (d, 1H), 7.8 (s, 2H),8.65 (s, 1H).

MS: 480.6 (M+H)⁺.

The starting material was prepared as follows:

3-Bromopropan-1-ol (20 ml, 20 mmol) was added dropwise to a solution of1-methylpiperazine (29 ml, 26 mmol) in ethanol (200 ml). Potasiumcarbonate (83 gr, 60 mmol) was added and the mixture was refluxed for 20hours. After cooling, the solid was filtered and the filtrate wasevaporated. The residue was triturated with ether, filtrate andevaporated. The residue was distilled at about 60-70° C. under about 0.2mm Hg to give 1-(3-hydroxypropyl)-4-methylpiperazine (17 g, 53%).

¹H NMR Spectrum: (CDCl₃) 1.72 (m, 2H); 2.3 (s, 3H); 2.2-2.8 (m, 8H); 2.6(t, 2H); 3.8 (t, 2H); 5.3 (br s, 1H).

EXAMPLE 18

A suspension of4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g,0.6 mmol), (prepared as described in Example 4),1-(3-chloropropyl)piperidine (0.12 g, 0.72 mmol) and potassium carbonate(0.125 g, 0.9 mmol) in DMF (5 ml) was stirred at 95° C. for 2 hours.After cooling, the precipitate was filtered. The filtrate was dilutedwith methylene chloride and purified by column chromatography elutingwith methanol/ethyl acetate/methylene chloride (1/4/5) followed bymethanol/methylene chloride (1/9) followed by methanol saturated withammonia/methylene chloride (1/9). The fractions containing the expectedproduct were combined and evaporated to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)cinnoline(27 mg, 10%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.35-1.5 (m, 1H), 1.6-1.8 (m, 3H),1.8-1.9 (m, 2H), 2.32 (m, 2H), 2.45 (s, 3H), 2.95 (dd, 2H), 3.3 (m, 2H),3.55 (d, 2H), 4.18 (s, 3H), 4.45 (m, 2H), 6.35 (s, 1H), 7.15 (dd, 1H),7.3 (d, 1H), 7.78 (s, 1H), 7.82 (s, 1H), 8.75 (s, 1H).

MS: 465.6 (M+H)⁺.

EXAMPLE 19

Using an analogous procedure to that described in Example 15,4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g,0.6 mmol), (prepared as described in Example 4), was reacted with1-(2-hydroxyethyl)pyrrolidine (0.11 ml, 0.9 mmol) to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)cinnoline(30 mg, 12%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.8-2.0 (br s, 2H), 2.1 (br s, 2H),2.45 (s, 3H), 3.12 (br s, 2H), 3.7 (br s, 2H), 3.82 (s, 2H), 4.17 (s,3H), 4.7 (br s, 2H), 6.35 (s, 0.5H, partly exchanged), 7.15 (dd, 1H),7.3 (d, 1H), 7.8 (s, 1H), 7.85 (s, 1H), 8.75 (s, 1H).

MS: 437.5 (M+H)⁺.

EXAMPLE 20

Under nitrogen, diethyl azodicarboxylate (0.19 ml, 1.2 mmol) was addeddropwise to a suspension of4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g,0.6 mmol), (prepared as described in Example 4), triphenylphosphine(0.31 g, 1.2 mmol) and 3-(4-methylsulfonylpiperazin-1-yl)propan-1-ol(0.2 g, 0.9 mmol) in DMF (4 ml). The mixture was stirred for 2 hours atambient temperature. Methylene chloride was added and the mixture waspoured onto silica and eluted with ethyl acetate/methylene chloride(1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/4)followed by methanol/methylene chloride (1/9). The fractions containingthe expected product were combined and evaporated. The residue wastriturated with diethyl ether and filtered. The solid was washed withether and dried under vacuum to give4-(4-fluoro-2-methylindol-5-yl)oxy-6-methoxy-7-(3-(4-methylsulfonylpiperazin-1-yl)propoxy)cinnoline(90 mg, 28%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.3-2.4 (m, 2H), 2.45 (s, 3H), 3.05(s, 3H), 3.1-3.3 (m, 4H), 3.45 (m, 2H), 3.7-3.85 (m, 4H), 4.07 (s, 3H),4.45 (t, 2H), 6.35 (s, 0.5H, partly exchanged), 7.15 (dd, 1H), 7.32 (d,1H), 7.8 (s, 1H), 7.85 (s, 1H), 8.75 (s, 1H).

MS: 544.5 (M+H)⁺.

The starting material was prepared as follows:

Methanesulfonyl chloride (966 μl, 12.5 mmol) was added dropwise to asolution of 1-benzylpiperazine (2 g, 11.3 mmol) and triethylamine (1.74ml, 12.5 mmol) in dry methylene chloride (30 ml) cooled at 0° C. Afterstirring for 1 hour at ambient temperature, the mixture was partitionedbetween water and methylene chloride. The organic layer was separated,washed with water, brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography eluting with methylene chloride/ethylacetate (7/3) to give 1-benzyl-4-methylsulfonylpiperazine (2.5 g, 87%).

¹H NMR Spectrum: (CDCl₃) 2.6 (m, 4H), 2.8 (s, 3H), 3.3 (m, 4H), 3.6 (s,2H), 7.25-7.4 (m, 5H).

MS: 255 (M+H)⁺.

A suspension of 1-benzyl-4-methylsulfonylpiperazine (2.5 g, 9.8 mmol)and cyclohexane (30 ml) in ethanol (70 ml) containing 20% palladiumhydroxide on carbon (500 mg) was stirred at 80° C. for 4 hours. Themixture was cooled, filtered and the filtrate was evaporated to give1-methylsulfonylpiperazine (1.58 g, 98%).

¹H NMR Spectrum: (CDCl₃) 2.8 (s, 3H), 4.0 (m, 4H), 3.2 (m, 4H).

MS: 165.3 (M+H)⁺.

A suspension of 1-methylsulfonylpiperazine (1.58 g, 9.6 mmol),3-bromo-1-propanol (1.13 ml, 12 mmol) and potassium carbonate (1.73 g,12 mmol) in acetonitrile (10 ml) was stirred at 40° C. for 4 hoursfollowed by 2 hours at 70° C. The mixture was cooled, filtered and thefiltrate was evaporated under vacuum. The residue was purified by columnchromatography eluting with methylene chloride/methanol (97/3 followedby 95/5) to give 3-(4-methylsulfonylpiperazin-1-yl)propan-1-ol (1.95 g,91%).

¹H NMR Spectrum: (CDCl₃) 1.8 (m, 2H), 2.7 (m, 6H), 2.8 (s, 3H), 3.3 (m,4H), 3.82 (t, 2H), 4.5 (br s, 1H).

MS: 223.4 (M+H)⁺.

EXAMPLE 21

Using an analogous procedure to that described in Example 20,4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g,0.6 mmol), (prepared as described in Example 4), was reacted with4-(2-hydroxyethyl)pyridine (0.11 g, 0.9 mmol), (Zhur. Obshchei. Khim.1958, 28, 103-110), to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(4-pyridyl)ethoxy)cinnoline(0.15 g, 57%).

¹H NMR Spectrum: (DMSOd₆) 2.45 (s, 3H), 3.25 (t, 2H), 4.05 (s, 3H), 4.6(t, 2H), 6.32 (s, 1H), 7.1 (dd, 1H), 7.28 (d, 1H), 7.45 (d, 2H), 7.57(s, 1H), 7.85 (s, 1H), 8.35 (s, 1H), 8.55 (d, 2H).

MS: 445.5 (M+H)⁺.

EXAMPLE 22

Using an analogous procedure to that described in Example 20,4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g,0.5 mol), (prepared as described in Example 4), was reacted with3-(hydroxymethyl)pyridine (60 μl, 0.9 mmol) to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyridylmethoxy)cinnoline(80 mg, 32%).

¹H NMR Spectrum: (DMSOd₆) 2.45 (s, 3H), 4.08 (s, 3H), 5.5 (s, 2H), 6.32(s, 1H), 7.1 (dd, 1H), 7.28 (d, 1H), 7.5 (dd, 1H), 7.6 (s, 1H), 7.95 (s,1H), 8.0 (d, 1H), 8.35 (s, 1H), 8.62 (d, 1H), 8.8 (s, 1H).

MS: 431 (M+H)⁺.

EXAMPLE 23

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically acceptablesalt thereof hereafter compound X), for therapeutic or prophylactic usein humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 LactosePh.Eur 223.75 Croscarmellose sodium 6.0 Maize statch 15.0Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesiumstearate 1.5 (e) Injection I (50 mg/ml) Compound X   5.0% w/v 1N Sodiumhydroxide solution   15.0% v/v 0.1N Hydrochloric acid (to adjust pH to7.6) Polyethylene glycol 400   4.5% w/v Water for injection to 100% (f)Injection II 10 mg/ml) Compound X   1.0% w/v Sodium phosphate BP   3.6%w/v 0.1N Sodium hydroxide solution   15.0% v/v Water for injection to100% (g) Injection III (1 mg/ml, buffered to pH6) Compound X   0.1% w/vSodium phosphate BP  2.26% w/v Citric acid  0.38% w/v Polyethyleneglycol 400   3.5% w/v Water for injection to 100%Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

REFERENCE EXAMPLE 1 2-methyl-1H-pyrrolo[2,3-b]pyridin-5-ol

To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (920 mg, 6.2 mmol)(Heterocycles 50, (2) 1065-1080, 1999) in methylene chloride (20 ml) wasadded benzyltriethylammonium chloride (37 mg, 0.16 mmol) followed bysodium hydroxide powder (771 mg, 19.2 mmol). The mixture was cooled to0° C. and benzylsulfonyl chloride (991 μl, 7.77 mmol) was addeddropwise. The mixture was stirred at 0° C. for 15 minutes followed by 2hours at ambient temperature. The mixture was filtered over diatomaceousearth and the filtrate was evaporated under vacuum. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (20/80 followed by 30/70). The fractions containing the expectedproduct were combined and evaporated to give5-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.69 g; 94%)

¹H NMR Spectrum: (DMSO d₆) 3.86 (s, 3H); 6.78 (d, 1H); 7.6-7.7 (m, 3H);7.72 (dd, 1H); 7.88 (d, 1H); 8.02-8.12 (m, 3H).

MS: 289.47 [M+H]⁺.

A solution of 5-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(900 mg, 3.12 mmol) in THF (22.5 ml) was added dropwise to a solution oflithium diisopropylamide (prepared from nBu-Li (2.5M in hexane); 2.5 ml)and diisopropylamine (874 μl) in THF (13.5 ml)) cooled at −25° C. andthe mixture was stirred for 30 minutes. Methyl iodide (215 μl, 3.44mmol) in THF (9 ml) was then added dropwise and the mixture was stirredfor 10 minutes at −25° C., left to warm up to ambient temperature andstirred for 15 minutes. The mixture was then poured onto ice/water. Themixture was then extracted with ethyl acetate. The organic layer wasseparated, washed with water, brine, dried (MgSO₄), filtered andevaporated. The residue was purified by column chromatography, elutingwith ethyl acetate/petroleum ether (20/80 followed by 30/70). Thefractions containing the expected product were combined and evaporatedto give 5-methoxy-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(805 mg, 85%).

¹H NMR Spectrum: (DMSOd₆) 2.7 (s, 3H); 3.82 (s, 3H); 6.51 (d, 1H); 7.49(d, 1H); 7.59 (dd, 2H); 7.7 (m, 1H); 8.0-8.1 (m, 3H).

MS: 303.5 [M+H]⁺.

A solution of5-methoxy-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (950 mg,3.14 mmol) and 40% aqueous sodium hydroxide (106 ml) in methanol (160ml) was heated at reflux for 30 minutes. After cooling, the mixture waspoured onto cooled water and extracted with ethyl acetate. The organiclayer was separated, washed with water, brine, dried (MgSO₄), filteredand evaporated. The residue was purified by column chromatographyeluting with ethyl acetate/petroleum ether (1/1). The fractionscontaining the expected product were combined and evaporated to give5-methoxy-2-methyl-1H-pyrrolo[2,3-b]pyridine (462 mg, 91%).

¹H NMR Spectrum: (DMSO d₆) 2.38 (s, 3H); 3.8 (s, 3H); 6.06 (d, 1H); 7.39(d, 1H); 7.82 (d, 1H).

MS: 163.3 [M+H]⁺.

A solution of boron tribromide (64 μl, 0.68 mmol) in methylene chloride(200 l) was added to a solution of5-methoxy-2-methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.308 mmol) inmethylene chloride (4 ml) cooled at −30° C. The mixture was left to warnup to ambient temperature and further stirred for 3 hours. The mixturewas poured onto ice. The pH was adjusted to 6.2 with 6N aqueous sodiumhydroxide followed by 2 N aqueous hydrogen chloride. The mixture wasextracted with ethyl acetate. The organic layer was washed with water,followed by brine and dried (MgSO₄), filtered and the filtrate wasevaporated. The residue was purified by column chromatography, elutingwith with methylene chloride followed by methylene chloride/methanol(98/2 followed by 95/5). The fractions containing the expected productwere combined and evaporated to give2-methyl-1H-pyrrolo[2,3-b]pyridin-5-ol (45 mg, quantitative). ¹H NMRSpectrum: (DMSO d₆) 2.4 (s, 3H); 5.96 (s, 1H); 7.12 (d, 1H); 7.69 (d,1H); 8.9 (s, 1H); 11.07 (br s, 1H).

MS: 149.2 [M+H]⁺.

1. A compound of the formula I:

wherein: either any one of G₁, G₂, G₃, G₄ and G₅ is nitrogen and theother four are —CH—, or G₁, G₂, G₃, G₄ and G₅ are all —CH—; Z is —O—,—NH—, —S—, —CH₂— or a direct bond; Z is linked to any one of G₁, G₂, G₃and G₄ which is a free carbon atom; n is an integer from 0 to 5; any ofthe substituents R¹ may be attached at any free carbon atom of theindole, azaindole or indazole group, such free carbon atoms may be G₁,G₂, G₃, G₄ or G₅ or may be at the 3-position of the indole, azaindole orindazole group; m is an integer from 0 to 3; R^(a) represents hydrogen;R^(b) represents hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,aminoC₁₋₄alkyl, C₁₋₃alkylaminoC₁₋₄alkyl, di(C₁₋₃alkyl)aminoC₁₋₄alkyl,C₂₋₅alkenylaminoC₁₋₄alkyl, C₂₋₅alkynylaminoC₁₋₄alkyl, —C₁₋₅alkyl(ring A)wherein ring A is selected from azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholino and thiomorpholino and wherein ring A may bearone or more substituents selected from C₁₋₄alkyl, C₂₋₅alkenyl,C₂₋₅alkynyl, hydroxy, oxo, halogeno, cyano, cyanoC₁₋₄alkyl,C₁₋₄alkylsulphonyl and C₁₋₄alkanoyl; R¹ represents hydrogen, oxo,hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,aminoC₁₋₄alkyl, C₁₋₃alkylaminoC₁₋₄alkyl, di(C₁₋₃alkyl)aminoC₁₋₄alkyl,—C₁₋₅alkyl(ring B) wherein ring B is selected from azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl,N-ethylpiperazinyl, morpholino and thiomorpholino; R² representshydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C₁₋₃alkyl,C₁₋₃alkoxy, C₁₋₃alkylsulphanyl, —NR³R⁴ (wherein R³ and R⁴, which may bethe same or different, each represents hydrogen or C₁₋₃alkyl), or R⁵X¹—(wherein X¹ represents a direct bond, —O—, —CH₂—, —OC(O)—, —C(O)—, —S—,—SO—, —SO₂—, —NR⁶C(O)—, —C(O)NR⁷—, —SO₂NR⁸—, —NR⁹SO₂— or —13 NR¹⁰—(wherein R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), and R⁵ is selected from one of thefollowing twenty-two groups: 1) hydrogen, oxiranylC₁₋₄alkyl or C₁₋₅alkylwhich may be unsubstituted or which may be substituted with one or moregroups selected from hydroxy, fluoro, chloro, bromo and amino; 2)C₁₋₅alkylX²C(O)R¹¹ (wherein X² represents —O— or —NR¹²— (in which R¹²represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹¹C₁₋₃alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be thesame or different each represents hydrogen, C₁₋₅alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₅alkylX³R¹⁶ (wherein X³ represents —O—,—S—, —SO—, —SO₂—, —OC(O)—, —NR¹⁷C(O)—, —C(O)NR¹⁸, —SO₂NR¹⁹—, —NR²⁰SO₂—or —NR²¹— (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ each independentlyrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶represents hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 4-, 5- or6-membered saturated heterocyclic group with 1-2 heteroatoms, selectedindependently from O, S and N, which C₁₋₃alkyl group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno and C₁₋₄alkoxy andwhich cyclic group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl)); 4)C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²² (wherein X⁴ and X⁵ which may be the same ordifferent are each —O—, —S—, —SO—, —SO₂—, —NR²³C(O)—, —C(O)NR²⁴—,—SO₂NR²⁵—, —NR²⁶SO₂ or —NR²⁷— (wherein R²³, R²⁴, R²⁵, R²⁶ and R²⁷ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR² represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl); 5) R²⁸(wherein R²⁸ is a 4-, 5- or 6-membered saturated heterocyclic group(linked via carbon or nitrogen) with 1-2 heteroatoms, selectedindependently from O, S and N, which heterocyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁alkanoyl,C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl)); 6)C₁₋₅alkylR²⁸ (wherein R²⁸ is as defined herein); 7) C₂₋₅alkenylR²⁸(wherein R²⁸ is as defined herein); 8) C₂₋₅alkynylR²⁸ (wherein R²⁸ is asdefined herein); 9) R²⁹ (wherein R²⁹ represents a pyridone group, aphenyl group or a 5-6-membered aromatic heterocyclic group (linked viacarbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, whichpyridone, phenyl or aromatic heterocyclic group may carry up to 5substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR³⁰R³¹,—NR³²C(O)R³³ (wherein R³⁰, R³¹, R³² and R³³, which may be the same ordifferent, each represents hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, is 0 or1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with1-2 heteroatoms, selected independently from O, S and N, which cyclicgroup may bear one or more substituents selected from C₁₋₄alkyl)); 10)C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined herein); 11) C₂₋₅alkenylR²⁹(wherein R²⁹ is as defined herein); 12) C₂₋₅alkynylR²⁹ (wherein R²⁹ isas defined herein); 13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ represents —O—, —S—,—SO—, —SO₂—, —NR³⁴C(O)—, —C(O)NR³⁵—, —SO₂NR³⁶—, —NR³⁷SO₂— or —NR³⁸—(wherein R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as definedherein); 14) C₂₋₅alkenylX⁷R²⁹ (wherein X⁷ represents —O—, —S—, —SO—,—SO₂—, —NR³⁹C(O)—, —C(O)NR⁴⁰—, —SO₂NR⁴¹—, —NR⁴²SO₂— or —NR⁴³— (whereinR³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined herein); 15)C₂₋₅alkynylX⁸R²⁹ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—,—NR⁴⁴C(O)—, —C(O)NR⁴⁵—, —SO₂NR⁴⁶—, —NR⁴⁷SO₂— or —NR⁴⁸— (wherein R⁴⁴,R⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined herein); 16)C₁₋₄alkylX⁹C₁₋₄alkylX²⁹ (wherein X⁹ represents —O—, —S—, —SO—, —SO₂—,—NR⁴⁹C(O)—, —C(O)NR⁵⁰—, —SO₂NR⁵¹, —NR⁵²SO₂— or —NR⁵³— (wherein R⁴⁹, R⁵⁰,R⁵¹, R⁵² and R⁵³ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined herein); 17)C₁₋₄alkylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined herein); 18)C₂₋₅alkenyl which may be unsubstituted or which may be substituted withone or more groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl andN,N-di(C₁₋₄alkyl)aminosulphonyl; 19) C₂₋₅alkynyl which may beunsubstituted or which may be substituted with one or more groupsselected from hydroxy, fluoro, amino, C₁₋₄alkylamino,N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl andN,N-di(C₁₋₄alkyl)aminosulphonyl; 20) C₂₋₅alkenylX⁹C₁₋₄alkylR²⁸ (whereinX⁹ and R²⁸ are as defined herein); 21) C₂₋₅alkynylX⁹C₁₋₄alkylR²⁸(whereinX⁹ and R²⁸ are as defined herein); and 22)C₁₋₄alkylR⁵⁴(C₁₋₄alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹ is as defined herein,q is 0 or 1, r is 0 or 1, and R⁵⁴ and R⁵⁵ are each independentlyselected from hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl and a 4-, 5-or 6-membered saturated heterocyclic group with 1-2 heteroatoms,selected independently from O, S and N, which C₁₋₃alkyl group may bear 1or 2 substituents selected from oxo, hydroxy, halogeno and C₁₋₄alkoxyand which cyclic group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl), with theproviso that R⁵⁴ cannot be hydrogen); and additionally wherein anyC₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl group in R⁵X¹— may bear one ormore substituents selected from hydroxy, halogeno and amino); or a saltthereof.
 2. A compound according to claim 1 wherein Z is —O— or —NH—. 3.A compound according to claim 1 wherein G₁, G₂, G₃, G₄ and G₅ are all—CH— which may be substituted as defined in claim
 1. 4. A compoundaccording to claim 3 wherein the optionally substituted indole moiety offormula II¹:

wherein R¹, R^(b) and n are as defined in claim 1, is selected from4-fluoro-2-methylindol-5-yl, 2-methylindol-5-yl, 2-methylindol-6-yl,2,3-dimethylindol-5-yl, 1-methylindol-5-yl, 1,2-dimethylindol-5-yl,4-fluoroindol-5-yl, 6-fluoroindol-5-yl and indol-5-yl.
 5. A compoundaccording to claim 1 wherein R^(b) is hydrogen.
 6. A compound accordingto claim 1 wherein R¹ represents methyl, ethyl, trifluoromethyl orhalogeno.
 7. A compound according to claim 1 wherein R² representshydroxy, halogeno, nitro, trifluoromethyl, C₁₋₃alkyl, cyano, amino orR⁵X¹— [wherein X¹ is as defined in claim 1 and R⁵ is selected from oneof the following twenty groups: 1) C₁₋₃alkyl which may be unsubstitutedor which may be substituted with one or more groups selected fromfluoro, chloro and bromo, or C₂₋₃alkyl which may be unsubstituted orsubstituted with one or more groups selected from hydroxy and amino; 2)2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,3-N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,3-(carbamoyloxy)propyl, or 2-(N-methyl-N-(butoxycarbonyl)amino)ethyl; 3)C₂₋₃alkylX³R¹⁶ (wherein X³ is as defined in claim 1 and R¹⁶ is a groupselected from C₁₋₃alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl,piperidinyl, piperazinyl, azetidinyl, imidazolidinyl andtetrahydropyranyl which group is linked to X³ through a carbon atom andwhich C₁₋₃alkyl group may bear 1 or 2 substituents selected fromhydroxy, halogeno and C₁₋₂alkoxy and which cyclopentyl, cyclohexyl,pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl ortetrahydropyranyl group may bear one substituent selected from oxo,hydroxy, halogeno, cyano, C₁₋₂cyanoalkyl, C₁₋₂alkyl, C₁₋₂hydroxyalkyl,C₁₋₂alkoxy, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₂alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino)); 4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are asdefined in claim 1 and R²² represents hydrogen or C₁₋₂alkyl); 5) R²⁸(wherein R²⁸ is as defined in claim 1); 6) C₁₋₃alkylR⁵⁹ (wherein R⁵⁹ isa group selected from pyrrolidinyl, piperazinyl, piperidinyl,azetidinyl, imidazolidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked toC₁₋₃alkyl through a carbon atom and which group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₂cyanoalkyl, C₁₋₂alkyl, C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, C₁₋₂alkanoyl,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₂alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino)) or C₂₋₃alkylR⁶⁰ (wherein R⁶⁰ is a group selected frommorpholino, thiomorpholino, azetidin-1-yl, pyrrolidin-1-yl,piperazin-1-yl and piperidino which group may bear 1 or 2 substituentsselected from oxo, hydroxy, halogeno, cyano, C₁₋₂cyanoalkyl, C₁₋₂alkyl,C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, C₁₋₂alkanoyl, C₁₋₂alkoxyC₁₋₃alkyl,C₁₋₂alkylsulphonyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₂alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl,morpholino and thiomorpholino)); 7) R²⁹ (wherein R²⁹ is as defined inclaim 1); 8) C₁₋₄alkylR²⁹ (wherein R²⁹ is as defined in claim 1); 9)1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined in claim 1); 10)1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined in claim 1); 11)C₁₋₃alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined in claim 1); 12)1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined in claim 1);13) 1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined in claim1); 14) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined inclaim 1); 15) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁹ are as definedin claim 1); 16) C₂₋₅alkenyl which may be unsubstituted or which may besubstituted with one or more fluorine atoms or with one or two groupsselected from hydroxy, fluoro, amino, C₁₋₄alkylamino,N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl andN,N-di(C₁₋₄alkyl)aminosulphonyl; 17) C₂₋₅alkynyl which may beunsubstituted or which may be substituted with one or more fluorineatoms or with one or two groups selected from hydroxy, fluoro, amino,C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,N-C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl; 18)C₂₋₃alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined in claim1); 19) C₂₋₃alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined inclaim 1); and 20) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹, q,r, R⁵⁴ and R⁵⁵ are as defined in claim 1); and additionally wherein anyC₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl group in R⁵X¹— may bear one ormore substituents selected from hydroxy, halogeno and amino].
 8. Acompound according to claim 1 wherein one of the R² substituents isR⁵X¹—, wherein R⁵ and X¹ are as defined in claim 1, and the substituentR⁵X¹—, is at the 7-position of the cinnoline ring.
 9. A compoundaccording to claim 7 wherein one of the R² substituents is R⁵X¹—,wherein R⁵ and X¹ are as defined in claim 7, and the substituent R⁵X¹—is at the 7-position of the cinnoline ring.
 10. A compound according toclaim 8 wherein the R² substituent at the 6-position of the cinnolinering is hydrogen, methoxy or cyano.
 11. A compound selected from:4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline,4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(piperidin-4-ylmethoxy)cinnoline,4-(4-fluoro-2-methylindol-5-yloxy)-7-(R)-(2-hydroxy-3-(piperidin-1-yl)propoxy)-6-methoxycinnoline,4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)cinnoline,7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline,4-(4-fluoro-2-methylindol-5-yloxy)-7-(R)-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxycinnoline,4-(4-fluoro-2-methylindol-5-yl)oxy-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)cinnoline,and4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)cinnoline,or a salt thereof.
 12. A compound according to any one of claims 1 to 11in the form of a pharmaceutically acceptable salt.
 13. A process for thepreparation of a compound of formula I or salt thereof which comprises:(a) the reaction of a compound of the formula III:

(wherein R^(a), R² and m are as defined in claim 1 and L¹ is adisplaceable moiety), with a compound of the formula IV:

(wherein R^(b), R¹, G₁, G₂, G₃, G₄, G₅, Z and n are as defined in claim1); (b) a compound of formula I or a salt thereof wherein at least oneR² is R⁵X¹ wherein R⁵ is as defined in claim 1 and X¹ is —O—, —S—,—OC(O)— or —NR¹⁰— (wherein R¹⁰ independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) may be prepared by the reaction of acompound of the formula V:

(wherein R^(a), R^(b), Z, G₁, G₂, G₃, G₄, G₅, R¹, R² and n are asdefined in claim 1 and X¹ is as herein defined in this section and s isan integer from 0 to 2) with a compound of formula VI:  R⁵-L¹  (I)(wherein R⁵ is as defined in claim 1 and L¹ is as defined herein); (c) acompound of the formula I or a salt thereof wherein at least one R² isR⁵X¹ wherein R⁵ is as defined in claim 1 and X¹ is —O—, —S—, —OC(O)— or—NR¹⁰— (wherein R¹⁰ represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) may be prepared by the reaction of a compound ofthe formula VII:

with a compound of the formula VII:R⁵—X¹—H  (VIII) (wherein R^(a), R^(b), R¹, R², R⁵, G₁, G₂, G₃, G₄, G₅, Zand n are as defined in claim 1 and L¹ and s are as defined herein andX¹ is as defined herein in this section); (d) a compound of the formulaI or a salt thereof wherein at least one R² is R⁵X¹ wherein X¹ is asdefined in claim 1 and R⁵ is C₁₋₅alkylR⁶², wherein R⁶² is selected fromone of the following nine groups: 1) X¹⁰C₁₋₃alkyl (wherein X¹⁰represents —O—, —S—, —SO₂—, —NR⁶³C(O)— or —NR⁶⁴SO₂— (wherein R⁶³ and R⁶⁴which may be the same or different are each hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl); 2) NR⁶⁵R⁶⁶ (wherein R⁶⁵ and R⁶⁶ which may be thesame or different are each hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl);3) X¹¹C₁₋₅alkylX⁵R²² (wherein X¹¹ represents —O—, —S—, —SO₂—,—NR⁶⁷C(O)—, —NR⁶⁸SO₂— or —NR⁶⁹— (wherein R⁶⁷, R⁶⁸, and R⁶⁹ which may bethe same or different are each hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and X⁵ and R²² are as defined in claim 1); 4) R²⁸(wherein R²⁸ is as defined in claim 1); 5) X¹²R²⁹ (wherein X¹²represents —O—, —S—, —SO₂—, —NR⁷⁰C(O)—, —NR⁷¹SO₂—, or —NR⁷²— (whereinR⁷⁰, R⁷¹, and R⁷² which may be the same or different are each hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined in claim 1); and6) X¹³C₁₋₃alkylR⁹ (wherein X¹³ represents —O—, —S—, —SO₂—, —NR⁷³C(O)—,—NR⁷⁴SO₂— or —NR⁷⁵— (wherein R⁷³, R⁷⁴ and R⁷⁵ each independentlyrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is asdefined in claim 1); 7) R²⁹ (wherein R²⁹ is as defined in claim 1); 8)X¹³C₁₋₄alkylR²⁸ (wherein X¹³ and R²⁸ are as defined in claim 1); and 9)R⁵⁴(C₁₋₄alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein q, r, X⁹, R⁵⁴ and R⁵⁵ are asdefined in claim 1); maybe prepared by reacting a compound of theformula IX:

(wherein X¹, R^(a), R^(b), R¹, R², G₁, G₂, G₃, G₄, G₅, Z and n are asdefined in claim 1 and L¹ and s are as defined herein) with a compoundof the formula X:R⁶²—H  (X) (wherein R⁶² is as defined herein) to give a compound of theformula I or salt thereof, (e) a compound of the formula I or a saltthereof wherein one or more of the substituents (R²)_(m) is representedby —NR⁷⁶R⁷⁷, where one (and the other is hydrogen) or both of R⁷⁶ andR⁷⁷ are C₁₋₃alkyl, may be effected by the reaction of a compound offormula I wherein the substituent (R²)_(m) is an amino group and analkylating agent; (f) a compound of the formula I or a salt thereofwherein X¹ is —SO— or —SO₂— may be prepared by oxidation from thecorresponding compound in which X¹ is —S— or —SO— (when X¹ is —SO₂— isrequired in the final product); and when a salt of a compound of formulaI is required, reaction of the compound obtained with an acid or basewhereby to obtain the desired salt.
 14. A pharmaceutical compositionwhich comprises a compound of the formula I as defined in any one ofclaims 1-11, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically acceptable excipient or carrier. 15.A method for producing an antiangiogenic and/or vascular permeabilityreducing effect in a warm-blooded animal in need thereof which comprisesadministering to said animal an effective amount of a compound offormula I as defined in any one of claims 1-11, or a pharmaceuticallyacceptable salt thereof.